Method for producing 5-hydroxypiperidine-2-carboxylic acid

ABSTRACT

A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by the formula (10) below: 
     
       
         
         
             
             
         
       
     
     the method including removing the protecting group from the hydroxyl group in a compound represented by formula (7) below: 
     
       
         
         
             
             
         
       
     
     (wherein P represents a protecting group, R 3  represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms) to synthesize a compound represented by formula (8) below: 
     
       
         
         
             
             
         
       
     
     (wherein R 3  represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).

The present application is a Divisional application of U.S. applicationSer. No. 15/108,141, filed Jun. 24, 2016, which is a National Stage ofinternational Patent Application No. PCT/JP2014/084518 filed Dec. 26,2014, which claims priority to Japanese Application No. 2013-272766filed Dec. 27, 2013. The disclosures of U.S. application Ser. No.15/108,141 and International Patent Application No. PCT/JP2014/084518are incorporated by reference herein in their entireties.

TECHNICAL FIELD

The present invention relates to a method for producing(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid and syntheticintermediates thereof (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylicacid, which is produced by the method of the present invention, isuseful as a synthetic intermediate for a β-lactamase inhibitor and thelike.

BACKGROUND ART

(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid is a usefulintermediate for the synthesis of an agent and the like that inhibitsβ-lactamases in bacteria exhibiting the resistance against the β-lactamclass of antibiotics, which β-lactamases are the major cause of theresistance in the bacteria.

A production method using glutamic acid or pyroglutamic acid as astarting raw material has been known as a method for producing(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid. Specifically,Patent Document 1 describes that a protected5-hydroxypiperidine-2-carboxylic acid compound as an intermediate ofN-protected oxo-azacycloalkylcarboxylic acids is produced frompyroglutamic acid as a starting raw material through the homologationprocess to increase carbon atoms and the cyclization process.

Moreover, Non-Patent Document 1 describes that a protected5-hydroxypiperidine-2-carboxylic acid compound is produced fromglutamine as a starting raw material through the homologation process toincrease carbon atoms and the cyclization process.

Non-Patent Document 2 describes that a mixture of stereoisomers of aprotected 5-hydroxypiperidine-2-carboxylic acid compound is producedfrom a protected glutamic acid compound as a starting raw materialthrough the homologation process to increase carbon atoms and thecyclization process.

Non-Patent Document 3 describes that a protected5-hydroxypiperidine-2-carboxylic acid compound is produced from aprotected pyroglutamic acid compound as a starting raw material throughthe homologation process to increase carbon atoms and the cyclizationprocess.

Patent Document 2 describes that a protected5-hydroxypiperidine-2-carboxylic acid compound is produced from aprotected pyroglutamic acid compound as a starting raw material throughthe homologation process to increase carbon atoms and the cyclizationprocess in one step.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: WO2010/126820-   Patent Document 2: WO2006/125974

Non-Patent Documents

-   Non-Patent Document 1: P. D. Bailey et al., Chem. Commun. 1996, 349.-   Non-Patent Document 2: P. D. Bailey et al., Tetrahedron Lett. 1988,    29, 2231.-   Non-Patent Document 3: M. A. Letavic et al., Bioorg. Med. Chem.    Lett. 2002, 12, 1387.

SUMMARY OF THE INVENTION Technical Problem

The method described in Patent Document 1 to produce(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid requires a veryexpensive iridium catalyst to be used and therefore is not suitable forthe industrial production.

The production method described in Non-Patent Document 1 is difficult tobe employed in the industrial production because the method alsorequires an expensive rhodium catalyst to be used and, furthermore,comprises the step of using diazomethane, which is difficult to use inindustrial applications.

The production method described in Non-Patent Document 2 is likewisedifficult to be employed in the industrial production because the methodalso comprises the step of using diazomethane, which is difficult to usein industrial applications, and further comprises a problem regarding anobtainable compound, in which the compound is obtained as a mixture ofstereoisomers.

The production methods described in Non-Patent Document 3 and PatentDocument 2 are likewise difficult to be employed in the industrialproduction because the methods comprise the step of using TMSdiazomethane, which is expensive and difficult to use in industrialapplications. Furthermore, the production method described in PatentDocument 2 requires an expensive rhodium catalyst to be used. Either ofthe production methods described in Non-Patent Document 3 and PatentDocument 2 requires the reaction to be performed at a quite lowtemperature and therefore is difficult to be employed in the industrialproduction.

In view of the above-mentioned problems, an object of the presentinvention is to provide a method for producing(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid and syntheticintermediates thereof including achiral and chiral molecules, the methodavailable for practical use in the industrial production.

Solution to Problem

The inventors have intensively studied to solve the above-describedproblems and consequently found that optically active substances of(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acids can beefficiently synthesized by using particular synthetic intermediates, andthereby completed the present invention.

That is, the present invention is as follows.

<1> A method for producing(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by theformula (10) below:

the method comprising (i) the step 4 of:

removing the protecting group from the hydroxyl group in a compoundrepresented by the formula (7) below:

(wherein P represents a protecting group, R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms) to synthesize acompound represented by the formula (8) below:

(wherein R³ represents an alkyl group containing 1 to 4 carbon atoms,and A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).<2> The method for producing(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid according to <1>,the method further comprising (ii) the step 5 of:(a) in the compound (8), hydrolyzing the ester groups, allowing one ofthe carboxyl groups to react with the hydroxyl group to allow thelactonization, and further decarboxylating the other carboxyl group; or(b) in the compound (8), hydrolyzing the ester groups, decarboxylatingone of the carboxyl groups to form a stereoisomeric mixture of a2-monocarboxylic acid, and then isomerizing and lactonizing thestereoisomeric mixture;to synthesize a compound represented by the formula (9) below:

(wherein A represents an alkyl group containing 1 to 10 carbon atoms, anaryl group containing 6 to 12 carbon atoms, an alkyloxy group containing1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbonatoms).<3> The method for producing(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid according to <1>or <2>, further comprising (iii) the step 6 of:

cleaving the amide bond in the compound (9) and hydrolyzing the lactonein the compound (9) to synthesize(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid.

<4> The method for producing(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid according to <2>or <3>, wherein the step of decarboxylating the carboxyl group in thestep 5(a) or the step 5(b) is performed in the presence of an organicbase.<5> A method for producing the compound represented by the formula (7)below:

(wherein P represents a protecting group, R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms), the method comprisingthe step 1 of:

protecting the hydroxyl group with a protecting group in a compoundrepresented by the formula (1) below:

(wherein X represents Cl, Br, or I, and R¹ represents a hydrogen atom oran optionally substituted alkyl group containing 1 to 4 carbon atoms) tosynthesize a compound represented by the formula (2) below:

(wherein X represents Cl, Br, or I, R¹ represents a hydrogen atom or anoptionally substituted alkyl group containing 1 to 4 carbon atoms, and Prepresents a protecting group)

and then reducing the ester group in the compound (2) to synthesize acompound represented by the formula (3) below:

(wherein X represents Cl, Br, or I, and P represents a protectinggroup).<6> The method for producing the compound (7) according to <5>, whereinthe method comprises (i) the step 2 of:

esterifying the hydroxyl group in the compound (3) to a sulfonate groupto synthesize a compound represented by the formula (4) below:

(wherein X represents Cl, Br, or I, R² represents an aryl groupcontaining 6 to 12 carbon atoms, an alkyl group containing 1 to 10carbon atoms, or an aralkyl group containing 7 to 20 carbon atoms)and allowing the compound (4) to react with a compound represented bythe formula (5) below:

(wherein R³ represents an alkyl group containing 1 to 4 carbon atoms,and A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)to synthesize a compound represented by the formula (6) below:

(wherein X represents Cl, Br, or 1, P represents a protecting group, R³represents an alkyl group containing 1 to 4 carbon atoms, and Arepresents an alkyl group containing 1 to 10 carbon atoms, an aryl groupcontaining 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms);and(ii) the step 3 of:

cyclizing the compound (6) to synthesize the compound represented by theformula (7) below:

(wherein P represents a protecting group, R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms).<7> The method for producing the compound (7) according to <6>, whereinthe reaction of the compound (4) with the compound (5) in the step 2 isperformed in the presence of an iodide salt.<8> The method for producing the compound (7) according to <6> or <7>,wherein the cyclizing reaction of the compound (6) in the step 3 isperformed in the presence of a quaternary ammonium salt.<9> The method for producing(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid according to anyone of <1> to <4>, wherein the compound (7) is synthesized by the methodaccording to any one of <5> to <8>.<10> A method for producing the compound represented by the formula (8),the method comprising (i) the step 4 of:

removing the protecting group from the hydroxyl group in the compoundrepresented by the formula (7) below:

(wherein P represents a protecting group, R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms) to synthesize thecompound represented by the formula (8) below:

(wherein R³ represents an alkyl group containing 1 to 4 carbon atoms,and A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).<11> A method for producing the compound represented by the formula (9),the method comprising(i) the step 4 of:

removing the protecting group from the hydroxyl group in the compoundrepresented by the formula (7) below:

(wherein P represents a protecting group, R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms) to synthesize thecompound represented by the formula (8) below:

(wherein R³ represents an alkyl group containing 1 to 4 carbon atoms,and A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)and (ii) the step 5 of:(a) in the compound (8), hydrolyzing the ester groups, allowing one ofthe carboxyl groups to react with the hydroxyl group to allow thelactonization, and further decarboxylating the other carboxyl group; or(b) in the compound (8), hydrolyzing the ester groups, decarboxylatingone of the carboxyl groups to form a stereoisomeric mixture of a2-monocarboxylic acid, and then isomerizing and lactonizing thestereoisomeric mixture;to synthesize the compound represented by the formula (9) below:

(wherein A represents an alkyl group containing 1 to 10 carbon atoms, anaryl group containing 6 to 12 carbon atoms, an alkyloxy group containing1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbonatoms).<12> A compound represented by the formula (9a) below:

(wherein A′ represents an aryl group containing 6 to 12 carbon atoms oran alkyl group containing 1 to 10 carbon atoms).<13> A compound or a salt thereof, the compound represented by theformula (11a) below:

(wherein A′ represents an aryl group containing 6 to 12 carbon atoms oran alkyl group containing 1 to 10 carbon atoms)or the formula (11b) below:

(wherein A′ represents an aryl group containing 6 to 12 carbon atoms oran alkyl group containing 1 to 10 carbon atoms).<14> A compound represented by the formula (8) below or a dicarboxylicacid salt thereof:

(wherein R³ represents an alkyl group containing 1 to 4 carbon atoms,and A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).<15> A compound represented by the formula (7) below:

(wherein P represents a protecting group, R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms).<16> A compound represented by the formula (6a) below:

(wherein X represents Cl, Br, or I, P′ represents a tetrahydropyranylgroup, methoxymethyl group, ethoxyethyl group, tert-butyl group, ortert-butyldimethylsilyl group, and R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms).<17> A compound represented by the formula (4a) below:

(wherein X represents Cl, Br, or I, P′ represents a tetrahydropyranylgroup, methoxymethyl group, ethoxyethyl group, tert-butyl group, ortert-butyldimethylsilyl group, and R² represents an aryl groupcontaining 6 to 12 carbon atoms, an alkyl group containing 1 to 10carbon atoms, or an aralkyl group containing 7 to 20 carbon atoms).<18> A compound represented by the formula (3a) below:

(wherein X represents Cl, Br, or I, and P′ represents atetrahydropyranyl group, methoxymethyl group, ethoxyethyl group,tert-butyl group, or tert-butyldimethylsilyl group).<19> A compound represented by the formula (2a) below:

(wherein X represents Cl, Br, or I, R¹ represents a hydrogen atom or anoptionally substituted alkyl group containing 1 to 4 carbon atoms, P″represents a tetrahydropyranyl group or ethoxyethyl group).

Advantageous Effect of the Invention

The present invention can provide(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid and a productionmethod therefor excellent in safety and operability and available forpractical use in the industrial production. Moreover, the presentinvention can provide novel synthetic intermediates for the productionof (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid.(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid, which is producedby the production method of the present invention, is available as astarting material in the production of a β-lactamase inhibitor and thelike.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows one aspect of the scheme for the synthesis of(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid. In the drawing, Xrepresents Cl, Br, or I. P represents a protecting group. A representsan alkyl group containing 1 to 10 carbon atoms, an aryl group containing6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms,or an aralkyloxy group containing 7 to 20 carbon atoms. R¹ represents ahydrogen atom or an optionally substituted alkyl group containing 1 to 4carbon atoms. R² represents an aryl group containing 6 to 12 carbonatoms, an alkyl group containing 1 to 10 carbon atoms, or an aralkylgroup containing 7 to 20 carbon atoms. R³ represents an alkyl groupcontaining 1 to 4 carbon atoms.

DESCRIPTION OF THE EMBODIMENTS

Now, the present invention will be described in detail.

In the present specification, the “compound represented by the formula(1)” may be referred to as the “compound (1)” and this is true of anycompounds represented by the other formulae.

In the present specification, Cl refers to a chlorine atom, Br refers toa bromine atom, I refers to an iodine atom, and Et refers to an ethylgroup.

[1] Production Method

The present invention is characterized in that optically activesubstances of (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acids areproduced by using a particular synthetic intermediate represented by theformula (8) below:

(wherein R³ represents an alkyl group containing 1 to 4 carbon atoms,and A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)or the formula (9) below:

(wherein A represents an alkyl group containing 1 to 10 carbon atoms, anaryl group containing 6 to 12 carbon atoms, or an alkyloxy groupcontaining 1 to 4 carbon atoms, an aralkyloxy group containing 7 to 20carbon atoms).

The compound (8) can be synthesized by ordinary procedures of organicchemistry and is preferably synthesized by the step 4 below.

The step 4 is a method to produce the compound represented by theformula (8) (the compound (8)) from a compound (7) as a raw material.

In the step 4, the protecting group can be removed from the hydroxylgroup in the compound represented by the formula (7) below:

(wherein P represents a protecting group, R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms) to synthesize thecompound represented by the formula (8) below:

(wherein R³ represents an alkyl group containing 1 to 4 carbon atoms,and A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).

Conditions commonly used in deprotection of each protection group can beemployed as conditions for the deprotection. Typically, an acid or acombination of an acid catalyst and an alcohol is used.

As the acid used for the deprotection, an inorganic acid such ashydrochloric acid, sulfuric acid, phosphoric acid and the like, or anorganic acid such as methanesulfonic acid, p-toluenesulfonic acid,oxalic acid, trifluoroacetic acid, formic acid, acetic acid and the likeis typically used and hydrochloric acid or p-toluenesulfonic acid ispreferably used.

As the acid catalyst, an inorganic acid such as hydrochloric acid,sulfuric acid and the like, or an organic acid such as methanesulfonicacid, p-toluenesulfonic acid and the like is typically used andhydrochloric acid or p-toluenesulfonic acid is preferably used.

As the alcohol, methanol, ethanol, n-propanol, 2-propanol, n-butanol orthe like is typically used and methanol is preferably used.

For example, in cases where P in the formula (7) is tetrahydropyranylgroup or ethoxyethyl group, hydrochloric acid is preferably applied as acatalyst in methanol solvent and the deprotection can easily be achievedin this method.

Out of compounds represented by the formula (8), a compound representedby the formula (8a) below:

(wherein Ac represents an acetyl group)is crystalline and therefore is easily isolated and purified bycrystallization after the deprotection so that the compound (8a) of highpurity can be synthesized. Because(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid of high purity canbe synthesized by performing the synthesis using the compound (8a) ofhigh purity, the compound (8a) is particularly preferable as thesynthetic intermediate. As the crystallization solvent, for example,toluene or a mixed solvent of toluene and heptane can be used.

Incidentally, R³ and A in the compound (8) are synonymous with R³ and Ain the compound (5) described below.

The compound (9) can be synthesized by ordinary procedures of organicchemistry and is preferably synthesized by the step 5 below.

The step 5 is a method to produce the compound represented by theformula (9) (the compound (9)) from the compound (8) as a raw material.The following step 5(a) or 5(b) is preferable as the step 5.

In the step 5(a), in the compound (8), the ester groups are hydrolyzed,one of the carboxyl groups is allowed to react with the hydroxyl groupto allow the lactonization, and the other carboxyl group is furtherdecarboxylated to synthesize the compound represented by the formula (9)below:

(wherein A represents an alkyl group containing 1 to 10 carbon atoms, anaryl group containing 6 to 12 carbon atoms, an alkyl group containing 1to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, or analkyloxy group containing 1 to 4 carbon atoms, an aralkyloxy groupcontaining 7 to 20 carbon atoms).

In the step 5(a), the ester groups in the compound (8) are firsthydrolyzed. A base is used in the hydrolysis of the ester groups.

Water, methanol, ethanol or the like is used as a reaction solvent.

As the base, sodium hydroxide, potassium hydroxide or the like can beused and sodium hydroxide is preferable among others.

The amount of the base to be used is typically 2- to 10-fold, preferably2- to 5-fold, relative to the amount of the compound (8) on the molarbasis.

The reaction temperature is not particularly limited but is typically 0°C. to 50° C. and preferably 0*C to 10° C.

The reaction time is not particularly limited but is typically for 1 to24 hours and preferably for 5 to 10 hours.

Next, one of the carboxyl groups is allowed to react with the hydroxylgroup to allow the lactonization after the ester groups in the compound(8) are hydrolyzed (ester degradation).

To perform the decarboxylation reaction after the lactonization, thedicarboxylic acid obtained by the ester degradation is first allowed toreact with a dehydrating agent to induce the carboxyl group in the cisposition with respect to the hydroxyl group at position 5 to belactonized.

As the dehydrating agent, a commonly used dehydrating agent such as, forexample, acetic anhydride, acetyl chloride, or thionyl chloride can beused.

The reaction solvent is not particularly limited as long as it does notinhibit the reaction, but acetic acid or a mixed solvent of acetic acidand toluene is preferably used.

The amount of the dehydrating agent to be used is typically 1- to20-fold, preferably 1- to 5-fold, relative to the amount of the compound(8), in which the ester groups have been hydrolyzed, on the molar basis.

The reaction temperature is not particularly limited but is typically 0°C. to 80° C. and preferably 30° C. to 60° C.

The reaction time is not particularly limited but is typically 1 to 12hours and preferably 2 to 5 hours.

After one of the carboxyl groups is lactonized, the other carboxyl groupis further decarboxylated.

When the other remaining carboxyl group is further decarboxylated,protonation occurs after the decarboxylation in a stereoselective mannerdue to the steric structure fixed by the lactonization and thus thecompound (9) in the 5-acyl-2-oxa-5-azabicyclo[2.2.2]octan-3-onestructure having a hydroxyl group and a carboxyl group in the cisposition is obtained.

The decarboxylation can proceed even by simply heating (simple heating)but the addition of an organic base such as triethylamine or pyridinepromotes the reaction and enables the reaction to proceed at a lowtemperature so that it is preferable.

The reaction temperature of the decarboxylation by simple heating istypically 100° C. to 130° C., while it is typically 60° C. to 90° C. incases where an organic base is added.

The reaction solvent is not particularly limited as long as it does notinhibit the reaction, but acetic acid or a mixed solvent of acetic acidand toluene is preferably used.

The amount of the organic base to be used is typically 0.1- to 2-fold,preferably 0.2- to 1-fold, relative to the amount of the lactonizedcompound (8) on the molar basis.

The reaction time is not particularly limited but is typically 1 to 12hours and preferably 2 to 5 hours.

In the step 5(b), in the compound (8), the ester groups are hydrolyzed,one of the carboxyl groups is decarboxylated to form a stereoisomericmixture of a 2-monocarboxylic acid, and then the stereoisomeric mixtureis isomerized and lactonized to synthesize the compound represented bythe formula (9) below:

(wherein A represents an alkyl group containing 1 to 10 carbon atoms, anaryl group containing 6 to 12 carbon atoms, or an alkyloxy groupcontaining 1 to 4 carbon atoms, an aralkyloxy group containing 7 to 20carbon atoms).

In the step 5(b), the hydrolysis of the ester groups in the compound (8)can be performed under the same conditions as those in the step 5(a).

After the ester groups in the compound (8) are hydrolyzed, one of thecarboxyl groups is decarboxylated to form a stereoisomeric mixture of a2-monocarboxylic acid.

In the step 5(b), since decarboxylation is first performed, thedicarboxylic acid obtained by the ester degradation is first subjectedto the decarboxylation to form a stereoisomeric mixture of a2-monocarboxylic acid.

The decarboxylation can proceed even by simply heating (simple heating)but the addition of an organic base such as triethylamine or pyridinepromotes the reaction and enables the reaction to proceed at a lowtemperature.

The reaction temperature of the decarboxylation by simple heating istypically 100° C. to 130° C., while it is typically 60° C. to 90° C. incases where an organic base is added.

The reaction solvent is not particularly limited as long as it does notinhibit the reaction, but acetic acid or a mixed solvent of acetic acidand methanol is preferably used.

The amount of the organic base to be used is typically 0.1- to 2-fold,preferably 0.2- to 1-fold, relative to the amount of the compound (8),in which the ester groups have been hydrolyzed, on the molar basis.

The reaction time is not particularly limited but is typically 1 to 12hours and preferably 2 to 5 hours.

Next, the stereoisomeric mixture is isomerized and lactonized. When thestereoisomeric mixture of the 2-monocarboxylic acid is isomerized andlactonized, a stereoisomer having the carboxyl group at position 2 inthe cis position with respect to the hydroxyl group at position 5 isimmediately lactonized with a dehydrating agent and a stereoisomerhaving the carboxyl group at position 2 in the trans position withrespect to the hydroxyl group at position 5 is isomerized to thestereoisomer having the carboxyl group at position 2 in the cis positionand then lactonized. Consequently, the compound (9) in the5-acyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one structure having a hydroxylgroup and a carboxyl group in the cis position is eventually obtainedfrom all types of the stereoisomers of the 2-monocarboxylic acid.Examples of an agent used in this step to perform dehydration andisomerization at the same time (a dehydrating andisomerizing/lactonizing agent) include acetic anhydride, a combinationof acetic anhydride and an amine, trifluoroacetic anhydride, acombination of trifluoroacetic anhydride and an amine, a combination ofa chlorocarbonate ester and an amine, and the like; and acetic anhydrideor a combination of acetic anhydride and an amine is preferable amongothers.

The amount of the dehydrating and isomerizing/lactonizing agent to beused is typically 1- to 20-fold, preferably 1- to 5-fold, relative tothe amount of the stereoisomeric mixture of the 2-monocarboxylic acid onthe molar basis.

In cases where a combination with an amine is used, pyridine,triethylamine or like is used as the amine, and triethylamine isparticularly preferable. The amount of the amine to be used is typically0.1- to 3-fold, preferably 0.2- to 1-fold, relative to the amount of thestereoisomeric mixture of the 2-monocarboxylic acid on the molar basis.

The reaction temperature is not particularly limited but is typically20° C. to 130° C. and preferably 60° C. to 90° C.

The reaction time is not particularly limited but is typically 1 to 12hours and preferably 2 to 5 hours.

In the steps 5(a) and 5(b), the synthetic schemes can also be performedwithout isolation and purification during the course of synthesis fromthe dicarboxylic acid derived by the ester degradation to the compound(9).

In that case, for example, the compound (9) can be synthesized bydissolving a disodium salt of the dicarboxylic acid in acetic acid,adding acetic anhydride for the intramolecular lactone formation, thenadding triethylamine and heating the mixture for the decarboxylation.

Moreover, for example, the compound (9) can also be synthesized bydissolving a disodium salt of the dicarboxylic acid in acetic acid,adding triethylamine followed by heating for the decarboxylation to forma stereoisomeric mixture of a 2-monocarboxylic acid, then adding aceticanhydride and heating the mixture. In this case, sodium acetate as aby-product can be deposited by addition of a poor solvent such astoluene and then removed by filtration.

In the step 5(a) or 5(b), in cases where A in the compound (9) to besynthesized is benzyloxy group, the compound is crystalline andtherefore is isolated and purified by crystallization so that thecompound (9) of high purity can be synthesized. Because(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid of high purity canbe synthesized by performing the synthesis using the compound (9) ofhigh purity, the compound (9) is particularly preferable as thesynthetic intermediate. As the crystallization solvent, for example, amixed solvent of toluene and heptane can be used.

Incidentally, A in the compound (9) is synonymous with A in the compound(5) described below.

Here, the compound (7) as a raw material can be synthesized by ordinaryprocedures of organic chemistry and is preferably synthesized by thesteps (1) to (3) below.

The step 1 is a step of producing a compound represented by the formula(3) (the compound (3)) from a compound represented by the formula (1)(the compound (1)) as a raw material.

The hydroxyl group in a compound represented by the formula (1) below:

(wherein X represents Cl, Br, or I, and R¹ represents a hydrogen atom oran optionally substituted alkyl group containing 1 to 4 carbon atoms)is protected with a protecting group to synthesize a compoundrepresented by the formula (2) below:

(wherein X represents Cl, Br, or I, R¹ represents a hydrogen atom or anoptionally substituted alkyl group containing 1 to 4 carbon atoms, and Prepresents a protecting group)and then the ester group in the compound (2) is reduced to synthesize acompound represented by the formula (3) below:

(wherein X represents Cl, Br, or I, and P represents a protectinggroup).

The compound (1) is a starting raw material of the step 1.

X in the formula (1) represents Cl, Br, or I, and X preferablyrepresents Cl. R¹ represents a hydrogen atom or an optionallysubstituted alkyl group containing 1 to 4 carbon atoms, and R¹preferably represents an optionally substituted alkyl group containing 1to 4 carbon atoms. Examples of the alkyl group include, for example,methyl group, ethyl group, n-propyl group, isopropyl group, n-butylgroup, isobutyl group, sec-butyl group, tert-butyl group, and the like.Examples of the substituent in the alkyl group include halogen atoms,alkoxy groups, and the like.

The compound (1) can easily be synthesized in accordance with a knownmethod, for example, a method described in Tetrahedron: Asymmetry,12(12), 1713 (2001) and the like. Moreover, a commercial product can beused as the compound (1) represented by the formula (1), in which Xrepresents Cl or Br and R¹ represents a methyl group or ethyl group.

First, the hydroxyl group in the compound (1) is protected with aprotecting group to synthesize the compound (2).

Ether protecting groups are preferable as the protecting group. It isthe reason for the use of an ether protecting group that etherprotecting groups are advantageous in the resistance to the basicconditions in the following steps. Incidentally, the oxygen atom bindingto the protecting group P in the compound (2) is derived from thehydroxyl group.

Examples of the protecting group include tetrahydropyranyl group,methoxymethyl group, ethoxyethyl group, tert-butyl group, ortert-butyldimethylsilyl group. Those protecting groups can be introducedby protecting a hydroxyl group through the reaction with a combinationof reaction agents, such as a combination of dihydropyran and an acidcatalyst, methoxymethyl chloride and diisopropylethylamine, ethyl vinylether and an acid catalyst, isobutylene and an acid catalyst, andtert-butyldimethylsilyl chloride and imidazole, respectively. Apreferable protecting group is tetrahydropyranyl group, methoxymethylgroup, ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilylgroup. Among others, tetrahydropyranyl group is preferable as theprotecting group because it has high safety.

In cases where tetrahydropyranyl group is used as the protecting group,for example, dihydropyran and an acid catalyst such as methanesulfonicacid, p-toluenesulfonic acid or pyridinium p-toluenesulfonate can beapplied to the compound (1) in a reaction solvent to obtain the compound(2).

The reaction solvent is not particularly limited as long as the reactionis allowed to proceed, but toluene, heptane, dichloromethane, ethylacetate and the like can be used. Moreover, the reaction can be allowedto proceed even in the absence of a solvent.

The amount of dihydropyran to be used is typically 1- to 10-fold,preferably 1- to 1.5-fold, relative to the amount of the compound (1) onthe molar basis.

The amount of the acid catalyst to be used is typically 0.001- to0.1-fold, preferably 0.002- to 0.02-fold, relative to the amount of thecompound (1) on the molar basis.

The reaction temperature is not particularly limited but is typically 0°C. to 80° C. and preferably 20° C. to 60° C.

The reaction time is not particularly limited but is typically 0.5 to 10hours and preferably 1 to 3 hours.

Moreover, X in the compound (2) represents Cl, Br, or I, and Xpreferably represents Cl.

In the compound (2), R¹ represents a hydrogen atom or an optionallysubstituted alkyl group containing 1 to 4 carbon atoms, and R¹preferably represents an optionally substituted alkyl group containing 1to 4 carbon atoms. Examples of the alkyl group include, for example,methyl group, ethyl group, n-propyl group, isopropyl group, n-butylgroup, isobutyl group, sec-butyl group, tert-butyl group, and the like.Examples of the substituent in the alkyl group include halogen atoms,alkoxy groups, and the like.

In the compound (2), P represents a protecting group, preferablytetrahydropyranyl group, methoxymethyl group, ethoxyethyl group,tert-butyl group, or tert-butyldimethylsilyl group, and particularlypreferably tetrahydropyranyl group.

Next, the ester group in the compound (2) is reduced to synthesize thecompound (3).

In the reduction of the ester group in the compound (2) to alcohol, ahydride reducing agent is preferably used. For example, an aluminiumhydride reducing agent such as lithium aluminium hydride,diisobutylaluminium hydride or sodium bis(methoxyethoxy)aluminiumhydride, or a boron hydride reducing agent such as sodium borohydride,lithium borohydride, calcium borohydride or borane can be used. Amongothers, an aluminium hydride reducing agent or lithium borohydride ispreferably used because of its high reaction activity in the reductionof esters.

For example, an aluminium hydride reducing agent can be applied to thecompound (2) in a reaction solvent to synthesize the compound (3).

The reaction solvent is not particularly limited as long as the reactionis allowed to proceed, but tetrahydrofuran, toluene and the like can beused. Moreover, the reaction can be allowed to proceed even in theabsence of a solvent.

The amount of the hydride reducing agent to be used is, in terms ofhydride, typically 2- to 10-fold, preferably 2- to 3-fold, relative tothe amount of the compound (2) on the molar basis.

The reaction temperature is not particularly limited but is typically 0°C. to 80° C. and preferably 0° C. to 20° C.

The reaction time is not particularly limited but is typically 0.5 to 10hours and preferably 1 to 3 hours.

Incidentally, X and P in the compound (3) are synonymous with X and P inthe compound (2).

The step 2 is a step of producing a compound represented by the formula(6) (the compound (6)) from the compound (3) as a raw material.

The hydroxyl group in the compound (3) is esterified with a sulfonategroup to synthesize a compound represented by the formula (4) below:

(wherein X represents Cl, Br, or I, R² represents an aryl groupcontaining 6 to 12 carbon atoms, an alkyl group containing 1 to 10carbon atoms, or an aralkyl group containing 7 to 20 carbon atoms)and then the compound (4) is allowed to react with a compoundrepresented by the formula (5) below:

(wherein R³ represents an alkyl group containing 1 to 4 carbon atoms,and A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)to synthesize a compound represented by the formula (6) below:

(wherein X represents Cl, Br, or I, P represents a protecting group, R³represents an alkyl group containing 1 to 4 carbon atoms, and Arepresents an alkyl group containing 1 to 10 carbon atoms, an aryl groupcontaining 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).

First, the hydroxyl group in the compound (3) is esterified with asulfonate group to synthesize the compound (4).

In the esterification of the hydroxyl group in the compound (3) with asulfonate group, a combination of a commonly used alkylsulfonyl chlorideand a base, or a combination of a commonly used arylsulfonyl chlorideand a base can be employed. For example, a combination ofmethanesulfonyl chloride or p-toluenesulfonyl chloride and triethylaminecan be employed.

For example, an alkylsulfonyl chloride or arylsulfonyl chloride and abase can be applied to the compound (3) in a reaction solvent tosynthesize the compound (4).

The reaction solvent is not particularly limited as long as the reactionis allowed to proceed, but toluene, methylene chloride, tetrahydrofuran,ethyl acetate and the like can be used. Moreover, the reaction can beallowed to proceed even in the absence of a solvent.

Moreover, an organic base such as pyridine or triethylamine, or aninorganic base such as sodium bicarbonate or sodium hydroxide can beused as the base.

The amount of the alkylsulfonyl chloride or arylsulfonyl chloride to beused is typically 1- to 2-fold, preferably 1- to 1.2-fold, relative tothe amount of the compound (3) on the molar basis.

The amount of the base to be used is typically 1- to 2-fold, preferably1- to 1.5-fold, relative to the amount of the compound (3) on the molarbasis.

The reaction temperature is not particularly limited but is typically 0°C. to 50° C. and preferably 0° C. to 20° C.

The reaction time is not particularly limited but is typically 0.5 to 5hours and preferably 1 to 2 hours.

Incidentally, X and P in the compound (4) are synonymous with X and P inthe compound (2).

Moreover, in the compound (4), R² represents an aryl group containing 6to 12 carbon atoms, an alkyl group containing 1 to 10 carbon atoms, oran aralkyl group containing 7 to 20 carbon atoms, preferably representsan aryl group containing 6 to 7 carbon atoms, an alkyl group containing1 to 3 carbon atoms, or an aralkyl group containing 7 to 11 carbonatoms, and more preferably represents a methyl group. Examples of thearyl group include, for example, phenyl group, tolyl group, naphthylgroup, biphenyl group, and the like. Examples of the alkyl groupinclude, for example, methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, isobutyl group, sec-butyl group,tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group,and the like. Examples of the aralkyl group include, for example, benzylgroup, phenethyl group, and the like.

Next, the compound (4) is allowed to react with compound (5) tosynthesize the compound (6).

In the compound (5), R³ represents an alkyl group containing 1 to 4carbon atoms, and preferably an alkyl group containing 1 to 2 carbonatoms. Examples of the alkyl group include, for example, methyl group,ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutylgroup, sec-butyl group, tert-butyl group, and the like.

Moreover, in the compound (5), A represents an alkyl group containing 1to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, analkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy groupcontaining 7 to 20 carbon atoms, preferably represents an aryl groupcontaining 6 to 10 carbon atoms, an alkyl group containing 1 to 3 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 11 carbon atoms, and more preferablyrepresents a methyl group. Examples of the aryl group include, forexample, phenyl group, naphthyl group, biphenyl group, and the like.Examples of the alkyl group include, for example, methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptylgroup, octyl group, and the like. Examples of the alkyloxy group includemethyloxy group, ethyloxy group, n-propyloxy group, isopropyloxy group,n-butyloxy group, isobutyloxy group, tert-butyloxy group, and the like.Examples of the aralkyloxy group include benzyloxy group, phenethyloxygroup, and the like.

A commercial product can be used as the compound (5). A compound (5) canbe available, for example, from TateyamaKasei Co., Ltd.

When the reaction between the compound (4) and the compound (5) isperformed, a base is necessary to generate an anion at the α-position inthe compound (5). For this purpose, the reaction is preferably performedin the presence of, for example, a strong base such as sodium hydride,sodium hexamethyldisilazane, lithium hexamethyldisilazane, lithiumdiisopropylamide, sodium tert-butoxide, potassium tert-butoxide, sodiumethoxide, sodium methoxide, sodium hydroxide, or potassium hydroxide; ora weak base such as cesium carbonate, potassium carbonate, or sodiumcarbonate. The reaction is preferably performed in the presence of abase, such as, among others, sodium hydride, sodium tert-butoxide,potassium tert-butoxide, sodium ethoxide, cesium carbonate or potassiumcarbonate.

The amount of the base to be used is typically not less than 0.8-fold,preferably 0.8- to 1.2-fold in cases of a strong base and 0.8- to 3-foldin cases of a weak base, relative to the amount of the substrate (thecompound (5)) on the molar basis.

The reaction solvent is not particularly limited as long as it candissolve the substrate, but aprotic polar solvents such asdimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone and the like; alcohol solvents such as methanol,ethanol, propanol, butanol and the like; ether solvents such astetrahydrofuran, diethyl ether, methyl-tert-butyl ether,methylcyclopropyl ether and the like; and mixed solvents thereof with ahydrocarbon solvent such as toluene, hexane, or heptane, or with ahalohydrocarbon solvent such as dichloromethane, chloroform, or1,2-dichloroethane are preferably used. Even more preferably,dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone,tetrahydrofuran, mixed solvents thereof with toluene, a mixed solvent ofethanol and toluene are used.

The reaction temperature is not particularly limited but is typically 0°C. to 130° C. and preferably 20° C. to 80° C.

The reaction time is not particularly limited but is typically for 1 to24 hours and preferably 1 to 5 hours.

In this step, an iodide salt is preferably added for the purpose ofpromoting the reaction and increasing the selectivity. As examples ofthe iodide salt, iodide salts represented by MI (M refers to an alkalimetal) are preferable and, among others, iodide salts such as potassiumiodide, sodium iodide and the like are preferable. The amount of thesesalts to be added is 0.02- to l-fold, preferably 0.2- to 0.4-fold,relative to the amount of the substrate (the compound (4)) on the molarbasis.

The amount of the compound (5) to be used for the compound (4) is 1- to2-fold, preferably 1- to 1.2-fold, relative to the amount of thecompound (4) on the molar basis.

Incidentally, in the compound (6), X and P are synonymous with X and Pin the compound (2), and R³ and A are synonymous with R³ and A in thecompound (5).

The step 3 is a step of producing a compound represented by the formula(7) (the compound (7)) from the compound (6) as a raw material.

The compound (6) is cyclized to synthesize a compound represented by theformula (7) below:

(wherein P represents a protecting group, R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms).

A base is required in the step 3. As the base, for example, a strongbase such as sodium hydride, sodium hexamethyldisilazane, lithiumhexamethyldisilazane, lithium diisopropylamide, sodium tert-butoxide,potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodiumhydroxide, or potassium hydroxide; or a weak base such as cesiumcarbonate, potassium carbonate, or sodium carbonate is used, and sodiumhydride, sodium tert-butoxide, potassium tert-butoxide, cesium carbonateor potassium carbonate is preferably used.

The amount of the base to be used is typically not less than 1-fold,preferably 1- to 2-fold in cases of a strong base and 1- to 3-fold incases of a weak base, relative to the amount of the substrate (thecompound (6)) on the molar basis.

The reaction solvent is not particularly limited as long as it candissolve the substrate (the compound (6)), but aprotic polar solventssuch as dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone or the like; or ether solvents such astetrahydrofuran, diethyl ether, methyl-tert-butyl ether,methylcyclopropyl ether and the like; and mixed solvents thereof with ahydrocarbon solvent such as toluene, hexane, or heptane, or with ahalohydrocarbon solvent such as dichloromethane, chloroform, or1,2-dichloroethane are preferably used, and N,N-dimethylformamide,N-methylpyrrolidone, tetrahydrofuran, and mixed solvents thereof withtoluene are even more preferably used.

The reaction temperature is not particularly limited but is typically 0°C. to 130° C., preferably 10° C. to 50° C. in cases of a strong base,and preferably 80° C. to 130° C. in cases of a weak base.

The reaction time is not particularly limited but is typically for 1 to24 hours and preferably 1 to 6 hours.

This step is preferably performed in the presence of a quaternaryammonium salt such as tetrabutylammonium bromide and the like for thepurpose of promoting the reaction and increasing the selectivity. Theamounts of these salts to be used are 0.02- to 1-fold, preferably 0.2-to 0.4-fold, relative to the amount of the substrate (the compound (6))on the molar basis.

Moreover, the step 2 and the step 3 can also be performed in serieswithout isolation and purification of the compound (6) during the courseof synthesis. In that case, the step 3 can be performed by adding a baseto the reaction mixture after the reaction of the step 2 has beencompleted.

Incidentally, in the compound (7), P is synonymous with P in thecompound (2), and R³ and A are synonymous with R³ and A in the compound(5).

In the present invention,(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid is preferablysynthesized with the following step 6.

The step 6 is a step of producing a compound represented by the formula(10) (the compound (10)) from the compound (9) as a raw material.

The lactone in the compound (9) is hydrolyzed and the amide bond in thecompound (9) is cleaved to synthesize(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by theformula (10) below:

The hydrolysis of the lactone and the cleavage of the amide bond in thecompound (9) may be allowed to proceed at the same time.

Commonly used conditions can be employed in the cleavage of the amidebond. For example, in cases where A is an alkyl group or aryl group, thecleavage can easily be achieved by applying a strong acid as a catalyst,such as hydrochloric acid, hydrobromic acid and the like, in a reactionsolvent.

As the reaction solvent, water, or aqueous solvents such as aqueousdioxane, aqueous dimethoxyethane, aqueous acetone and the like are used.

The amount of the strong acid to be used is typically 1- to 10-fold,preferably 1- to 2-fold, relative to the amount of the compound (9) onthe molar basis.

The reaction temperature is not particularly limited but is typically 0°C. to 100° C. and preferably 80° C. to 100° C.

The reaction time is not particularly limited but is typically 1 to 12hours and preferably 3 to 6 hours.

In the hydrolysis of the lactone, an acid or a base, for example,hydrochloric acid or sodium hydroxide is used in accordance with acommonly employed hydrolysis procedure.

As the reaction solvent, water, methanol, ethanol and the like are used.

The amount of the acid or base to be used is typically 1- to 10-fold,preferably 1- to 2-fold, relative to the amount of the compound (9)after the cleavage of the amide bond on the molar basis.

The reaction temperature is not particularly limited but is typically 0°C. to 100° C. and preferably 60° C. to 100° C.

The reaction time is not particularly limited but is typically 1 to 12hours and preferably 8 to 12 hours.

In the step 6, in cases where the compound (9) is a compound representedby the formula (9a):

(wherein A′ represents an alkyl group containing 1 to 10 carbon atoms oran aryl group containing 6 to 12 carbon atoms),for example, the addition of hydrochloric acid followed by heatingenables the hydrolysis of the lactone and the acetyl group to beperformed at the same time.

In this case, because the resulting(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid is ahydrochloride, the removal of hydrochloric acid and the like can beachieved with ion exchange resins in accordance with a commonly employedprocedure for the purification of amino acids. Moreover, thehydrochloric acid is neutralized using lithium hydroxide or lithiumcarbonate to produce lithium chloride, or alternatively usingtriethylamine to produce triethylamine hydrochloride. Then the reactionmixture is concentrated and followed by the addition of an alcohol,acetone and the like, so that the lithium chloride and triethylaminehydrochloride can be removed.

Incidentally, in the compound (9a), A′ represents an alkyl groupcontaining 1 to 10 carbon atoms or an aryl group containing 6 to 10carbon atoms, and preferably represents an alkyl group containing 1 to 3carbon atoms or an aryl group containing 6 carbon atoms. Examples of thearyl group include, for example, phenyl group. Examples of the alkylgroup include, for example, methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, isobutyl group, sec-butyl group,tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group,and the like.

Moreover, because (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acidis crystalline, it can be purified by performing recrystallization. Asthe recrystallization solvent, for example, a water/ethanol mixedsystem, a methanol/acetone mixed system and the like can be used.

In the steps 1 to 5 of the present invention, it is preferable in thecompounds (1) to (9) that X represents Cl, R¹ and R³ represent an ethylgroup, R² represents a methyl group or p-tolyl group, A represents amethyl group or phenyl group, and P represents a tetrahydropyranyl groupor methoxymethyl group, ethoxyethyl group, tert-butyldimethylsilyl groupor ter-butyl group.

In the present invention,(2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid is preferablyproduced by coupling the sulfonate ester of an optically active4-halo-3-protected hydroxybutanol (the compound (4)), which is derivedfrom an optically active 4-halo-3-hydroxybutanoate ester (the compound(1)), to an acylaminomalonate diester (the compound (5)) to obtain anoptically active 2-acylamino-2-[4-halo-3-protectedhydroxybutyl]-malonate diester (the compound (6)); performingcyclization and deprotection on it to obtain an optically active1-acyl-5-hydroxypiperidine-2,2-dicarboxylate diester (the compound 8);and then hydrolyzing the ester, followed by (a) forming a lactone fromthe hydroxyl group at position 5 and one of the dicarboxylates atposition 2, and decarboxylating the remaining carboxylate, or (b)decarboxylating to form a stereoisomeric mixture of a 2-monocarboxylicacid, and isomerizing and lactonizing the 2-monocarboxylic acid, toobtain 5-acyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (the compound (9));and finally performing deprotection and hydrolysis. Accordingly theoptically active substances can be efficiently synthesized.

[2] Novel Compounds

The present invention relates to the novel compounds indicated below.These novel compounds are useful as synthetic intermediates for aβ-lactamase inhibitor and the like.

The novel compounds of the present invention can be produced by theproduction method of the present invention. Moreover, they can also besynthesized by ordinary procedures of organic chemistry since thisspecification has indicated the structures thereof.

(A) Compounds represented by the formula (2a) below:

(wherein X represents Cl, Br, or I, R¹ represents a hydrogen atom or anoptionally substituted alkyl group containing 1 to 4 carbon atoms, P″represents a tetrahydropyranyl group or ethoxyethyl group).

X represents Cl, Br, or I, and preferably Cl.

R¹ represents a hydrogen atom or an optionally substituted alkyl groupcontaining 1 to 4 carbon atoms, and preferably an optionally substitutedalkyl group containing 1 to 4 carbon atoms. Examples of the alkyl groupinclude, for example, methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, isobutyl group, sec-butyl group,tert-butyl group, and the like. Examples of the substituent in the alkylgroup include halogen atoms, alkoxy groups, and the like.

P″ represents a tetrahydropyranyl group, or ethoxyethyl group.

Among the compounds (2a), compounds represented by the formulae beloware particularly preferable:

(B) Compounds represented by the formula (3a) below:

(wherein X represents Cl, Br, or I, and P′ represents atetrahydropyranyl group, methoxymethyl group, ethoxyethyl group,tert-butyl group, or tert-butyldimethylsilyl group).

P′ represents a tetrahydropyranyl group, methoxymethyl group,ethoxyethyl group, tert-butyl group, or tert-butyldimethylsilyl group.

Incidentally, in the compounds (3a), X is synonymous with X in thecompound (2a).

Among the compounds (3a), compounds represented by the formulae beloware particularly preferable:

(C) Compounds represented by the formula (4a) below:

(wherein X represents Cl, Br, or I, P′ represents a tetrahydropyranylgroup, methoxymethyl group, ethoxyethyl group, tert-butyl group, ortert-butyldimethylsilyl group, and R² represents an aryl groupcontaining 6 to 12 carbon atoms, an alkyl group containing 1 to 10carbon atoms, or an aralkyl group containing 7 to 20 carbon atoms).

R² represents an aryl group containing 6 to 12 carbon atoms, an alkylgroup containing 1 to 10 carbon atoms, or an aralkyl group containing 7to 20 carbon atoms, preferably represents an aryl group containing 6 to7 carbon atoms, an alkyl group containing 1 to 3 carbon atoms, or anaralkyl group containing 7 to 11 carbon atoms, and more preferablyrepresents a methyl group. Examples of the aryl group include, forexample, phenyl group, tolyl group, naphthyl group, biphenyl group, andthe like. Examples of the alkyl group include, for example, methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexylgroup, heptyl group, octyl group, and the like. Examples of the aralkylgroup include, for example, benzyl group, phenethyl group, and the like.

Incidentally, in the compounds (4a), X is synonymous with X in thecompound (2a) and P′ is synonymous with P′ in the compound (3a).

Among the compounds (4a), compounds represented by the formulae beloware particularly preferable:

(D) Compounds represented by the formula (6a) below:

(wherein X represents Cl, Br, or 1, P′ represents a tetrahydropyranylgroup, methoxymethyl group, ethoxyethyl group, tert-butyl group, ortert-butyldimethylsilyl group, and R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms).

R³ represents an alkyl group containing 1 to 4 carbon atoms, andpreferably an alkyl group containing 1 to 2 carbon atoms. Examples ofthe alkyl group include, for example, methyl group, ethyl group,n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, and the like.

A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms,preferably represents an alkyl group containing 1 to 3 carbon atoms, anaryl group containing 6 to 10 carbon atoms, an alkyloxy group containing1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 11 carbonatoms, and more preferably represents a methyl group and, phenyl group.Examples of the aryl group include, for example, phenyl group, naphthylgroup, biphenyl group, and the like. Examples of the alkyl groupinclude, for example, methyl group, ethyl group, n-propyl group,isopropyl group, n-butyl group, isobutyl group, sec-butyl group,tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group,and the like. Examples of the alkyloxy group include methyloxy group,ethyloxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group,isobutyloxy group, tert-butyloxy group, and the like. Examples of thearalkyloxy group include benzyloxy group, phenethyloxy group, and thelike.

Incidentally, in the compounds (6a), X is synonymous with X in thecompound (2a) and P′ is synonymous with P′ in the compound (3a).

Among the compounds (6a), compounds represented by the formulae beloware particularly preferable:

(wherein Ac represents an acetyl group and Bz represents a benzoylgroup).(E) Compounds represented by the formula (7) below:

(wherein P represents a protecting group, R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms).

P represents a protecting group and preferably represents atetrahydropyranyl group, methoxymethyl group, ethoxyethyl group,tert-butyl group, or tert-butyldimethylsilyl group.

Incidentally, in the compounds (7), R³ and A are synonymous with R³ andA in the compound (6a).

Among the compounds (7), compounds represented by the formulae below areparticularly preferable:

(wherein Ac represents an acetyl group and Bz represents a benzoylgroup).(F) Compounds represented by the formula (8) below or dicarboxylic acidsalts thereof:

(wherein R³ represents an alkyl group containing 1 to 4 carbon atoms,and A represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).

Incidentally, in the compounds (8), R³ and A are synonymous with R³ andA in the compound (6a).

Among the compounds (8), compounds represented by the formulae below areparticularly preferable:

(wherein Ac represents an acetyl group and Bz represents a benzoylgroup).

Among these, the compound (8a) is preferable as a synthetic intermediatesince it is crystalline and thus can be isolated and purified bycrystallization.

(G) Compounds represented by the formula (9a) below:

(wherein A′ represents an alkyl group containing 1 to 10 carbon atoms oran aryl group containing 6 to 12 carbon atoms).

A′ represents an alkyl group containing 1 to 10 carbon atoms or an arylgroup containing 6 to 12 carbon atoms, and preferably represents analkyl group containing 1 to 3 carbon atoms or an aryl group containing 6carbon atoms. Examples of the alkyl group include, for example, methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexylgroup, heptyl group, octyl group, and the like. Examples of the arylgroup include phenyl group, naphthyl group and the like.

Among the compounds (9a), compounds represented by the formulae beloware particularly preferable:

(wherein Ac represents an acetyl group and Bz represents a benzoylgroup).(H) A compound or a salt thereof, the compound represented by theformula (11a) below:

(wherein A′ represents an alkyl group containing 1 to 10 carbon atoms oran aryl group containing 6 to 12 carbon atoms)or the formula (11b) below:

(wherein A′ represents an alkyl group containing 1 to 10 carbon atoms oran aryl group containing 6 to 12 carbon atoms).

Incidentally, in the compounds (11a) and (11b), A′ is synonymous with A′in the compound (9a).

Among the compounds (11a) or (11b), compounds represented by theformulae below are particularly preferable:

EXAMPLES

Now, the present invention will be described in further detail by way ofExamples but the present invention is not limited by these Examples.

[Example 1] Production of(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butan-1-ol (a Compound of theFormula (3), Wherein X═Cl, and P=Tetrahydropyranyl Group)

In a 50-mL reactor, 1.50 g (9 mmol) of ethyl(3S)-4-chloro-3-hydroxybutanoate ester (a compound of the formula (1),wherein X═Cl, and R¹=ethyl group), 1.51 g (18 mmol) of dihydropyran, 29μL (0.45 mmol) of methanesulfonic acid and 15 mL of toluene were placedand the mixture was stirred for 0.5 hour at room temperature, followedby the addition of 250 μL (1.8 mmol) of triethylamine to stop thereaction. This mixture was washed with water, dried, and thenconcentrated to obtain 3.14 g of an oily crude ethyl(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butanoate ester (a compound ofthe formula (2), wherein X═Cl, P=tetrahydropyranyl group, and R¹=ethylgroup).

¹H-NMR (400 MHz, CDCl₃) δ1.23 (3H, m), 1.44-1.85 (6H, m), 2.58-2.80 (2H,m), 3.47-3.95 (4H, m), 4.17 (2H, m), 4.20-4.37 (1H, m), 4.73-4.80 (1H,m).

Next, the obtained crude ethyl(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butanoate ester (a compound ofthe formula (2), wherein X═Cl, P=tetrahydropyranyl group, and R¹=ethylgroup) was dissolved in 15 mL of dry tetrahydrofuran (hereinafterreferred to as “THF”), and 0.34 g (9 mmol) of lithium aluminium hydridewas added thereto and the mixture was stirred for 2 hours at 5° C.,followed by the addition of 1 mL of ethyl acetate and then 1 mL of waterto degrade an excess amount of the reducing agent and stop the reaction.This mixture was filtered through Celite and purified by silica gelcolumn chromatography to obtain 1.43 g of an oil of(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butan-1-ol (a compound of theformula (3), wherein X═Cl, and P=tetrahydropyranyl group) (the totalyield through the two steps: 73%).

¹H-NMR (400 MHz, CDCl₃) δ1.45-2.08 (8H, m), 3.35-4.13 (8H, m), 4.68-4.76(1H, m).

[Example 2] Production of(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl methanesulfonate ester(a Compound of the Formula (4), Wherein X═Cl, P=Tetrahydropyranyl Group,and R²=Methyl Group)

In a 50-mL reactor, 1.43 g (6.8 mmol) of the(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butan-1-ol (a compound of theformula (3), wherein X═Cl, and P=tetrahydropyranyl group) obtained inExample 1, 1.05 mL (7.5 mmol) of triethylamine and 14 mL of toluene wereplaced, and 0.56 mL (7.18 mmol) of methanesulfonyl chloride was addedthereto at 5° C. and the mixture was stirred for 1 hour at 5° C. Thisreaction liquid was washed with water, dried, and then concentrated toobtain 2.13 g of an oily crude(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl methanesulfonate ester(a compound of the formula (4), wherein X═Cl, P=tetrahydropyranyl group,and R²=methyl group) (yield: 97%).

¹H-NMR (400 MHz, CDCl₃) δ1.48-1.60 (4H, m), 1.72-1.85 (2H, m), 1.97-2.20(2H, m), 3.02 (3H, s), 3.50-4.12 (5H, m), 4.30-4.45 (2H, m), 4.68 (1H,m).

[Example 3] Production of(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl methanesulfonate ester(a compound of the formula (4), wherein X═Cl, P=tetrahydropyranyl group,and R²=methyl group)

In a 1-L reactor, 30 g (180.18 mmol) of ethyl(3S)-4-chloro-3-hydroxybutanoate ester (a compound of the formula (1),wherein X═Cl, and R¹=ethyl group), 18.16 g (216.22 mmol) ofdihydropyran, 0.44 g (1.80 mmol) of pyridinium p-toluenesulfonate and240 mL of toluene were placed and the mixture was stirred for 10 hoursat 45° C. to obtain a solution of ethyl(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butanoate ester (a compound ofthe formula (2), wherein X═Cl, P=tetrahydropyranyl group, and R¹=ethylgroup) in toluene.

Then, 70 mL (252.25 mmol) of a 70% solution of sodiumbis(methoxyethoxy)aluminium hydride in toluene was added to thisreaction liquid at 5° C. to 10° C. and the mixture was stirred for 7hours at 5° C. to 10° C. To this reaction liquid, 22.7 mL of water,3.1.59 g of magnesium sulfate, and 22.7 mL of water were addedsequentially at 5° C. to 10° C. and the mixture was stirred for 1 hourat 5° C. to 10° C. and left to stand overnight at 5° C., followed by thefiltration of solids. Then, the filtrate was washed with saturatedbrine, dried, and subsequently concentrated to obtain 247.39 g of(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butan-1-ol (a compound of theformula (3), wherein X═Cl, and P=tetrahydropyranyl group) in toluenesolution (the total yield through the two steps: 91%).

Next, to 237.3 g of this solution (containing 32.59 g (156.33 mmol) of(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butan-1-ol (a compound of theformula (3), wherein X═Cl, and P=tetrahydropyranyl group)), 17.37 g(171.96 mmol) of triethylamine was added and then 18.79 g (164.15 mmol)of methanesulfonyl chloride was added thereto at 5° C. to 12° C. and themixture was stirred for 1 hour at 5° C. to 10° C. This reaction liquidwas washed with water, dried, and then concentrated to obtain 51.72 g(pure content: 43.92 g) of crude(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl methanesulfonate ester(a compound of the formula (4), wherein X═Cl, P=tetrahydropyranyl group,and R²=methyl group) (the total yield through the three steps: 89%).

[Example 4-1] Production of (3S)-4-chloro-3-methoxymethyloxy-butylmethanesulfonate ester (a Compound of the Formula (4), Wherein X═Cl,P=Methoxymethyl Group, and R²=Methyl Group)

In a 50-mL reactor, 1.50 g (9.01 mmol) of ethyl(3S)-4-chloro-3-hydroxybutanoate ester (a compound of the formula (1),wherein X═Cl, and R¹=ethyl group), 2.02 mL (11.71 mmol) ofdiisopropylethylamine and 15 mL of toluene were placed and 1.18 g (11.71mmol) of methoxymethyl chloride was added thereto at room temperatureand the mixture was stirred at room temperature. After the completion ofthe reaction, the reaction liquid was washed with water, dried, and thenconcentrated to obtain 2.54 g of crude ethyl(3S)-4-chloro-3-methoxymethyloxy-butanoate ester (a compound of theformula (2), wherein X═Cl, P=methoxymethyl group, and R¹=ethyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.26 (3H, t, J=7.6 Hz), 2.60-2.75 (2H, m), 3.38(3H, s), 3.67 (2H, d, J=5.2 Hz), 4.15 (2H, q, J=7.3 Hz), 4.23 (1H, m),4.71 (2H, dd, J=6.8, 22 Hz).

Next, 2.54 g of this crude ethyl(3S)-4-chloro-3-methoxymethyloxy-butanoate ester (a compound of theformula (2), wherein X═Cl, P=methoxymethyl group, and R¹=ethyl group)was dissolved in 14 mL of toluene, and then 2.75 mL (9.91 mmol) of a 70%solution of sodium bis(methoxyethoxy)aluminium hydride in toluene wasadded thereto at 5° C. to 10° C. and the mixture was stirred for 1 hourat 5° C. to 10° C. To this reaction liquid, 1.8 mL of water, 0.56 g ofsodium sulfate, and 0.68 g of magnesium sulfate were added sequentiallyat 5° C. to 10° C., and the mixture was stirred for 1 hour at 5° C. to10° C. and filtered to remove solids. Then, the filtrate was washed withsaturated brine, dried, and subsequently concentrated to obtain asolution of (3S)-4-chloro-3-methoxymethyloxy-butan-1-ol (a compound ofthe formula (3), wherein X═Cl, P=methoxymethyl group) in toluene.

¹H-NMR (400 MHz, CDCl₃) δ1.78-1.95 (2H, m), 3.43 (3H, s), 3.58-3.67 (2H,m), 3.98 (1H, m), 4.74 (2H, dd, J=7.2, 24 Hz).

Next, 1.57 mL (11.29 mmol) of triethylamine was added to this solutionand then 0.83 mL (10.72 mmol) of methanesulfonyl chloride was addedthereto at 5° C. to 10° C. and the mixture was stirred for 1 hour at 5°C. to 10° C. This reaction liquid was washed with water, dried, and thenconcentrated to obtain 1.39 g of (3S)-4-chloro-3-methoxymethyloxy-butylmethanesulfonate ester (a compound of the formula (4), wherein X═Cl,P=methoxymethyl group, and R²=methyl group) (the total yield through thethree steps: 62%).

¹H-NMR (400 MHz, CDCl₃) δ1.98-2.15 (2H, m), 3.01 (3H, s), 3.40 (3H, s),3.59-3.68 (2H, m), 3.92 (1H, m), 4.36 (1H, m), 4.71 (2H, dd, J=8.0, 13.6Hz).

[Example 4-2] Production of (3S)-4-chloro-3-(1-ethoxyethyloxy)-butylmethanesulfonate ester (a Compound of the Formula (4), Wherein X═Cl,P=Ethoxyethyl Group, and R²=Methyl Group)

In a 1-L reactor, 5.02 g (30.13 mmol) of ethyl(3S)-4-chloro-3-hydroxybutanoate ester (a compound of the formula (1),wherein X═Cl, and R¹=ethyl group), 2.39 g (33.14 mmol) of ethyl vinylether, 0.08 g (0.30 mmol) of pyridinium p-toluenesulfonate and 25 mL oftoluene were placed and the mixture was stirred for 3 hours at 40° C. toobtain a solution of ethyl (3S)-4-chloro-3-(1-ethoxyethyloxy)-butanoateester (a compound of the formula (2), wherein X═Cl; P=ethoxyethyl group,and R¹=ethyl group) in toluene.

¹H-NMR (400 MHz, CDCl₃) δ1.18-1.36 (9H, m), 2.58-2.77 (2H, m), 3.23-3.75(4H, m), 4.10-4.35 (3H, m), 4.82 (1H, m).

Then, 70 mL (252.25 mmol) of a 70% solution of sodiumbis(methoxyethoxy)aluminium hydride in toluene was added to thisreaction liquid at 5° C. to 10° C. and the mixture was stirred for 1hour at 5° C. to 10° C. To this reaction liquid, 3.25 mL of water, 9.53g of magnesium sulfate, and 3.25 mL of water were added sequentially at5° C. to 10° C., and the mixture was stirred for 4 hours at 5° C. to 10°C. and filtered to remove solids. Then, the filtrate was washed withsaturated brine, dried, and subsequently concentrated to obtain 5.81 g(pure content: 5.44 g) of (3S)-4-chloro-3-(1-ethoxyethyloxy)-butan-1-ol(a compound of the formula (3), wherein X═Cl, and P=ethoxyethyl group)in toluene solution (the total yield through the two steps: 92%).

¹H-NMR (400 MHz, CDCl₃) δ1.17-1.29 (3H, m), 1.30-1.37 (3H, m), 1.61-1.72(0.6H, m), 1.80-2.00 (2H, m), 3.02 (0.4H, m), 3.50-3.90 (6H, m),3.92-4.08 (1H, m), 4.79-4.86 (1H, m).

Next, to 4.44 g of this solution (containing 4.16 g (21.17 mmol) of(3S)-4-chloro-3-(l-ethoxyethyloxy)-butan-1-ol (a compound of the formula(3), wherein X ═Cl, and P=ethoxyethyl group)), 20 mL of toluene and 2.35g (23.29 mmol) of triethylamine were added and then 2.55 g (22.23 mmol)of methanesulfonyl chloride was added thereto at 5° C. to 15° C. and themixture was stirred for 0.5 hour at 5° C. to 10° C. This reaction liquidwas washed with water, dried, and then concentrated to obtain 10.83 g(pure content: 5.33 g) of crude (3S)-4-chloro-3-(1-ethoxyethyloxy)-butylmethanesulfonate ester (a compound of the formula (4), wherein X═Cl,P=ethoxyethyl group, and R²=methyl group) in toluene solution (yield:92%).

¹H-NMR (400 MHz, CDCl₃) δ1.20 (3H, t, J=5.9 Hz), 1.32 (3H, d, J=7.4 Hz),1.92-2.19 (2H, m), 2.99 (3H, s), 3.43-3.71 (4H, m), 3.88 (0.5H, m), 4.02(0.5H, m), 4.26-4.40 (2H, m), 4.78 (1H, m).

[Example 4-3] Production of(3S)-4-chloro-3-tert-butyldimethylsilyloxy-butyl methanesulfonate ester(a Compound of the Formula (4), Wherein X═Cl, P=Tert-ButyldimethylsilylGroup, and R²=Methyl Group)

In a 50-mL reactor, 5.00 g (30.01 mmol) of ethyl(3S)-4-chloro-3-hydroxybutanoate ester (a compound of the formula (1),wherein X═Cl, and R¹=ethyl group), 3.06 g (45.02 mmol) of imidazole and25 mL of dichloromethane were placed and 5.88 g (39.01 mmol) oftert-butyldimethylsilyl chloride and 1.18 g (11.71 mmol) ofmethoxymethyl chloride were added thereto on ice and the mixture wasstirred at room temperature. After the completion of the reaction, thereaction liquid was washed with water and with saturated aqueous sodiumbicarbonate solution, dried, and the concentrated to obtain 8.01 g ofcrude ethyl (3S)-4-chloro-3-tert-butyldimethylsilyloxy-butanoate ester(a compound of the formula (2), wherein X═Cl, P=tert-butyldimethylsilylgroup, and R¹=ethyl group) (yield: 95%).

¹H-NMR (400 MHz, CDCl₃) δ0.05 (3H, s), 0.11 (3H, s), 0.88 (9H, s), 1.26(3H, t, J=7.4 Hz), 2.49-2.73 (2H, m), 3.52 (2H, s), 4.14 (2H, m), 4.31(1H, m).

Next, 8.01 g of this crude ethyl(3S)-4-chloro-3-tert-butyldimethylsilyloxy-butanoate ester (a compoundof the formula (2), wherein X═Cl, P=tert-butyldimethylsilyl group, andR¹=ethyl group) was dissolved in 25 mL of toluene, and 9.5 mL (34.24mmol) of a 70% solution of sodium bis(methoxyethoxy)aluminium hydride intoluene was added thereto at 5° C. to 15° C. and the mixture was stirredfor 2.5 hours at 5° C. to 10° C. To this reaction liquid, 2.05 mL ofacetic acid and 5.55 mL of water were added sequentially at 5° C. to 10°C., and the mixture was stirred for 0.5 hour at room temperature andfiltered to remove solids. Then, the filtrate was washed with saturatedbrine, dried, and subsequently concentrated to obtain 4.66 g (purecontent: 4.28 g) of(3S)-4-chloro-3-tert-butyldimethylsilyloxy-butan-1-ol (a compound of theformula (3), wherein X═Cl, and P=tert-butyldimethylsilyl group) intoluene solution (yield: 63%).

¹H-NMR (400 MHz, CDCl₃) δ0.14 (6H, s), 0.92 (9H, s), 1.80-2.01 (3H, m),3.52 (2H, m), 3.81 (2H, m), 4.10 (1H, m).

Next, 23 mL of toluene and 2.17 mL (21.46 mmol) of triethylamine wereadded to this solution and then 2.35 g (20.49 mmol) of methanesulfonylchloride was added thereto at 5° C. to 10° C. and the mixture wasstirred for 1 hour at 5° C. to 10° C. This reaction liquid was washedwith water, dried, and then concentrated to obtain 6.09 g (pure content:5.46 g) of (3S)-4-chloro-3-tert-butyldimethylsilyloxy-butylmethanesulfonate ester (a compound of the formula (4), wherein X═Cl,P=tert-butyldimethylsilyl group, and R²=methyl group) in toluenesolution (yield: 96%).

¹H-NMR (400 MHz, CDCl₃) δ0.10 (6H, s), 0.89 (9H, s), 1.90-1.99 (l H, m),2.06-2.17 (1H, m), 3.02 (3H, s), 3.47 (2H, m), 4.03 (1H, m), 4.28-4.40(2H, m).

[Example 4-4] Production of (3S)-4-chloro-3-tert-butyloxy-butylmethanesulfonate ester (a compound of the formula (4), wherein X═Cl,P=tert-butyl group, and R²=methyl group)

In a 100-mL reactor, 7.51 g (45.11 mmol) of ethyl(3S)-4-chloro-3-hydroxybutanoate ester (a compound of the formula (1),wherein X═Cl, and R¹=ethyl group) and 18 mL of n-hexane were placed and0.47 g (4.51 mmol) of concentrated sulfuric acid and 6.17 g (110.07mmol) of isobutylene were added thereto on ice and the mixture wasstirred for 18 hours at 30-35° C. Then, the reaction liquid was washedwith saturated aqueous sodium bicarbonate solution, dried, thenconcentrated, and purified by silica gel chromatography to obtain 4.92 gof ethyl (3S)-4-chloro-3-tert-butyloxy-butanoate ester (a compound ofthe formula (2), wherein X═Cl, P=tert-butyl group, and R¹=ethyl group)(yield: 49%).

¹H-NMR (400 MHz, CDCl₃) δ1.20 (9H, s), 1.28 (3H, t, J=8 Hz), 2.51-2.76(2H, m), 3.48-3.60 (2H, m), 4.15 (3H, m).

Next, 4.92 g (22.11 mmol) of this crude ethyl(3S)-4-chloro-3-tert-butyloxy-butanoate ester (a compound of the formula(2), wherein X═Cl, P=tert-butyl group, and R¹=ethyl group) was dissolvedin 25 mL of toluene, and 8 mL (28.74 mmol) of a 70% solution of sodiumbis(methoxyethoxy)aluminium hydride in toluene was added thereto at 5°C. to 15° C. and the mixture was stirred for 2 hours at 5° C. to 10° C.To this reaction liquid, 0.77 mL of ethanol, 3.41 g of citric acid, and20 mL of water were added sequentially at 5° C. to 10° C. and themixture was stirred for 0.5 hour at 5° C. to 10° C., and the separatedorganic phase was washed with saturated brine, dried, then concentrated,and then purified by silica gel chromatography to obtain 3.29 g of(3S)-4-chloro-3-tert-butyloxy-butan-1-ol (a compound of the formula (3),wherein X═Cl and P=tert-butyl group) (yield: 82%).

¹H-NMR (400 MHz, CDCl₃) δ1.25 (9H, s), 1.80-1.88 (1H, m), 1.94-2.03 (1H,m), 2.58 (1H, brm), 3.44-3.56 (2H, m), 3.75 (1H, m), 3.83 (1H, m), 3.96(1H, m).

Next, to 2.25 g (12.47 mmol) of the obtained(3S)-4-chloro-3-tert-butyloxy-butan-1-ol (a compound of the formula (3),wherein X═Cl and P=tert-butyl group), 23 mL of toluene and 2.24 mL(16.21 mmol) of triethylamine were added and 1.01 mL (13.09 mmol) ofmethanesulfonyl chloride was added thereto at 5° C. to 10° C. and themixture was stirred for 2 hours at 5° C. to 10° C. This reaction liquidwas washed with water, dried, and then concentrated to obtain 4.23 g(pure content: 3.19 g) of (3S)-4-chloro-3-tert-butyloxy-butylmethanesulfonate ester (a compound of the formula (4), wherein X═Cl,P=tert-butyl group, and R²=methyl group) in toluene solution (yield:99%).

¹H-NMR (400 MHz, CDCl₃) δ1.23 (9H, s), 1.88-1.96 (1H, m), 2.12-2.21 (1H,m), 3.02 (3H, s), 3.39-3.57 (2H, m), 3.86 (1H, m), 4.35 (2H, m).

[Example 4-5] Production of (3S)-4-chloro-3-methoxymethyloxy-butylp-toluenesulfonate ester (a Compound of the Formula (4), Wherein X═Cl,P=Methoxymethyl Group, and R²=p-Tolyl Group)

To 2.22 g (pure content: 2.00 g, 11.86 mmol) of the(3S)-4-chloro-3-methoxymethyloxy-butan-1-ol (a compound of the formula(3), wherein X═Cl, P=methoxymethyl group) obtained in accordance withExample 4, 9 mL of toluene and 1.00 g (13.10 mmol) of pyridine wereadded, and 2.40 g (12.50 mmol) of p-toluenesulfonyl chloride and 29 mg(0.24 mmol) of 4-dimethylaminopyridine were added thereto at roomtemperature and the mixture was stirred for 16 hours at 40° C. Thisreaction liquid was washed with water, dried, then concentrated, andpurified by silica gel chromatography to obtain 1.75 g of(3S)-4-chloro-3-methoxymethyloxy-butyl p-toluenesulfonate ester (acompound of the formula (4), wherein X═Cl, P=methoxymethyl group, andR²=p-tolyl group) (yield: 46%).

¹H-NMR (400 MHz, CDCl₃) δ1.88-2.03 (2H, m), 2.46 (3H, s), 3.35 (3H, s),3.53-3.66 (2H, m), 3.87 (1H, m), 4.09-4.20 (4H, m), 4.61 (2H, m), 7.35(2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.4 Hz).

[Example 4-6] Production of (3S)-4-chloro-3-(1-ethoxyethyloxy)-butylp-toluenesulfonate ester (a Compound of the Formula (4), Wherein X═Cl,P=Ethoxyethyl Group, and R²=p-Tolyl Group)

To 1.31 g (pure content: 6.23 mmol) of the(3S)-4-chloro-3-(1-ethoxyethyloxy)-butan-1-ol (a compound of the formula(3), wherein X═Cl, and P=ethoxyethyl group) obtained in accordance withExample 4-2, 6.1 mL of toluene, 0.69 g (6.85 mmol) of triethylamine,1.19 g (6.23 mmol) of p-toluenesulfonyl chloride and 0.76 g (6.23 mmol)of 4-dimethylaminopyridine were added and the mixture was stirred for 33hours at 40° C. This reaction liquid was washed with water, dried, thenconcentrated, and purified by silica gel chromatography to obtain 0.95 g(pure content: 0.44 g) of (3S)-4-chloro-3-(1-ethoxyethyloxy)-butylp-toluenesulfonate ester (a compound of the formula (4), wherein X═Cl,P=ethoxyethyl group, and R²=p-tolyl group) (yield: 20%).

¹H-NMR (400 MHz, CDCl₃) δ1.12-1.38 (6H, m), 1.80-2.10 (2H, m), 2.43 (3H,s), 3.40-3.85 (4H, m), 3.93-4.23 (3H, m), 4.80 (1H, m), 7.36 (2H, m),7.80 (2H, m).

[Example 5] Production of diethyl(3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, R³=ethyl group, and A=methyl group)

In a 20-mL reactor, 0.10 g (0.46 mmol) of diethyl acetaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=methyl group) and 1 mL of toluene were placed, and 180 μL (0.46 mmol)of 20% sodium ethoxide was added thereto and the mixture was stirred for1.5 hours at 25° C. To this mixture, 0.5 mL of the toluene solutioncontaining 0.15 g (pure content: 0.13 g, 0.46 mmol) of the crude(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl methanesulfonate ester(a compound of the formula (4), wherein X═Cl, P=tetrahydropyranyl group,and R²=methyl group) obtained in Example 2, 0.08 g (0.46 mmol) ofpotassium iodide, and 1 mL of ethanol were added at 25° C. and heated toreflux overnight. Ethyl acetate was added to this reaction liquid andthe resulting reaction liquid was washed with water, dried, thenconcentrated, and purified by silica gel column chromatography to obtain0.12 g of diethyl(3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, R³=ethyl group, and A=methyl group) (yield: 63%).

[Example 6] Production of diethyl(3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, R³=ethyl group, and A=methyl group)

In a 50-mL reactor, 0.68 g (3.15 mmol) of diethyl acetaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=methyl group) and 3.4 mL of N,N-dimethylformamide were placed, and0.29 g (3.00 mmol) of sodium tert-butoxide was added thereto and themixture was stirred for 1 hour at 30° C. To this mixture, 4 mL of thetoluene solution containing 1.01 g (pure content: 0.86 g, 3.00 mmol) ofthe crude (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butylmethanesulfonate ester (a compound of the formula (4), wherein X═Cl,P=tetrahydropyranyl group, and R²=methyl group) obtained in Example 3and 0.10 g (0.6 mmol) of potassium iodide were added at 30° C. and themixture was stirred for 7.5 hours at 60° C. This reaction liquid waswashed with water, dried, and then concentrated to obtain 1.22 g (purecontent: 1.01 g) of crude diethyl(3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, R³=ethyl group, and A=methyl group) (yield: 83%).

¹H-NMR (400 MHz, CDCl₃) δ1.25 (6H, m), 1.15-1.83 (8H, m), 2.03 (3H, s),2.30-2.50 (2H, m), 3.47-3.95 (5H, m), 4.20-4.30 (4H, m), 4.61 and 4.72(1H, m), 6.80 (1H, brs).

[Example 7-1] Production of diethyl(3S)-2-acetylamino-2-(4-chloro-3-methoxymethyloxy-butyl)malonate ester(a Compound of the Formula (6), Wherein X ═Cl, P=Methoxymethyl Group,R³=Ethyl Group, and A=Methyl Group)

In a 30-mL reactor, 0.49 g (2.27 mmol) of diethyl acetaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=methyl group) and 2.5 mL of dimethylsulfoxide were placed, and 0.23 g(2.38 mmol) of sodium tert-butoxide was added thereto and the mixturewas stirred for 2 hours at 30° C. To this mixture, 2.5 mL of the toluenesolution containing 0.56 g (2.27 mmol) of the crude(3S)-4-chloro-3-methoxymethyloxy-butyl methanesulfonate ester (acompound of the formula (4), wherein X═Cl, P=methoxymethyl group, andR²=methyl group) obtained in Example 4 and 0.08 g (0.45 mmol) ofpotassium iodide were added at 30° C. and the mixture was stirred for 5hours at 80° C. An aliquot of 200 μL was withdrawn from this reactionliquid and ethyl acetate was added thereto and the resulting mixture waswashed with water, dried, and then concentrated to obtain 25 mg ofdiethyl (3S)-2-acetylamino-2-(4-chloro-3-methoxymethyloxy-butyl)malonateester (a compound of the formula (6), wherein X═Cl, P=methoxymethylgroup, R³=ethyl group, and A=methyl group) (yield: 94%).

¹H-NMR (400 MHz, CDCl₃) δ1.23 (6H, t, J=5.2 Hz), 1.33-1.50 (2H, m), 2.01(3H, s), 2.30-2.46 (2H, m), 3.36 (3H, s), 3.55 (2H, d, J=5.2 Hz), 3.67(1H, m), 4.21 (4H, q, J=7.3 Hz), 4.64 (2H, dd, J=7.2, 18 Hz), 6.77 (1H,brs).

[Example 7-2] Production of diethyl(3S)-2-acetylamino-2-(4-chloro-3-(1-ethoxyethyloxy)-butyl)malonate ester(a Compound of the Formula (6), Wherein X═Cl, P=Ethoxyethyl Group,R³=Ethyl Group, and A=Methyl Group)

In a 50-mL reactor, 4.95 g (22.82 mmol) of diethyl acetaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=methyl group) and 22 mL of N,N-dimethylformamide were placed, and 2.15g (22.40 mmol) of sodium tert-butoxide was added thereto and the mixturewas stirred for 1.5 hours at 40° C. To this mixture, 10.83 g (purecontent: 5.33 g, 19.41 mmol) of the toluene solution containing thecrude (3S)-4-chloro-3-(1-ethoxyethyloxy)-butyl methanesulfonate ester (acompound of the formula (4), wherein X═Cl, P=ethoxyethyl group, andR²=methyl group) obtained in Example 4-2, 4 mL of toluene and 0.69 g(4.16 mmol) of potassium iodide were added at 40° C. and the mixture wasstirred for 2 hours at 80° C. Toluene was added to this reaction liquidand the resulting reaction liquid was washed with water, dried, and thenconcentrated to obtain 7.64 g (pure content: 7.14 g; yield: 93%) ofdiethyl(3S)-2-acetylamino-2-(4-chloro-3-(1-ethoxyethyloxy)-butyl)malonate ester(a compound of the formula (6), wherein X═Cl, P=ethoxyethyl group,R³=ethyl group, and A=methyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.15-1.32 (12H, m), 1.30-1.60 (2H, m), 2.03(3H, s), 2.30-2.52 (2H, m), 3.47-3.83 (5H, m), 4.23 (4H, q, J=7.0 Hz),4.73 and 4.81 (1H, m), 6.78 (1H, brs).

[Example 7-3] Production of diethyl(3S)-2-acetylamino-2-(4-chloro-3-tert-butyldimethylsilyloxy-butyl)malonateester (a Compound of the Formula (6), Wherein X═Cl,P=Tert-Butyldimethylsilyl Group, R³=Ethyl Group, and A=Methyl Group)

In a 50-mL reactor, 1.15 g (5.29 mmol) of diethyl acetaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=methyl group) and 6.8 mL of N,N-dimethylformamide were placed, and0.50 g (5.19 mmol) of sodium tert-butoxide was added thereto and themixture was stirred for 1 hour at 40° C. To this mixture, 1.70 g (purecontent: 1.52 g, 4.81 mmol) of the toluene solution containing the crude(3S)-4-chloro-3-tert-butyldimethylsilyloxy-butyl methanesulfonate ester(a compound of the formula (4), wherein X═Cl, P=tert-butyldimethylsilylgroup, and R²=methyl group) obtained in Example 4-3, 1 mL of toluene and0.16 g (0.96 mmol) of potassium iodide were added at 40° C. and themixture was stirred for 4 hours at 80° C. Toluene was added to thisreaction liquid and the resulting reaction liquid was washed with water,dried, and then concentrated to obtain 2.10 g (pure content: 1.77 g;yield: 84%) of diethyl(3S)-2-acetylamino-2-(4-chloro-3-tert-butyldimethylsilyloxy-butyl)malonateester (a compound of the formula (6), wherein X═Cl,P=tert-butyldimethylsilyl group, R³=ethyl group, and A=methyl group).

¹H-NMR (400 MHz, CDCl₃) δ0.09 (6H, s), 0.90 (9H, s), 1.24 (6H, t, J=7.5Hz), 1.29-1.55 (2H, m), 2.02 (3H, s), 2.30-2.50 (2H, m), 3.42 (2H, m),3.83 (1H, m), 4.25 (4H, m), 6.75 (1H, brs).

[Example 7-4] Production of diethyl(3S)-2-acetylamino-2-(4-chloro-3-tert-butyloxy-butyl)malonate ester (aCompound of the Formula (6), Wherein X═Cl, P=Tert-Butyl Group, R³=EthylGroup, and A=Methyl Group)

In a 50-mL reactor, 0.87 g (4.00 mmol) of diethyl acetaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=methyl group) and 4.3 mL of N,N-dimethylformamide were placed, and0.38 g (3.92 mmol) of sodium tert-butoxide was added thereto and themixture was stirred for 1 hour at 40° C. To this mixture, 1.25 g (purecontent: 0.94 g, 3.64 mmol) of the toluene solution containing the crude(3S)-4-chloro-3-tert-butyloxy-butyl methanesulfonate ester (a compoundof the formula (4), wherein X═Cl, P=tert-butyl group, and R²=methylgroup) obtained in Example 4-4, 2 mL of toluene and 0.12 g (0.73 mmol)of potassium iodide were added at 40° C. and the mixture was stirred for2 hours at 80° C. Toluene was added to this reaction liquid and theresulting reaction liquid was washed with water, dried, thenconcentrated, and purified by silica gel chromatography to obtain 1.06 g(pure content: 0.95 g; yield: 69%) of diethyl(3S)-2-acetylamino-2-(4-chloro-3-tert-butyloxy-butyl)malonate ester (acompound of the formula (6), wherein X═Cl, P=tert-butyl group, R³=ethylgroup, and A=methyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.19 (9H, s), 1.25 (6H, t, J=7.2 Hz), 1.30-1.38(1H, m), 1.49-1.59 (1H, m), 2.03 (3H, s), 2.30-2.47 (2H, m), 3.33-3.49(2H, m), 3.65 (1H, m), 4.27 (4H, q, J=7.2 Hz), 6.78 (1H, brs).

[Example 7-5] Production of diethyl(3S)-2-acetylamino-2-(4-chloro-3-methoxymethyloxy-butyl)malonate ester(a compound of the formula (6), wherein X ═Cl, P=methoxymethyl group,R³=ethyl group, and A=methyl group)

In a 50-mL reactor, 1.04 g (4.81 mmol) of diethyl acetaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=methyl group) and 5.4 mL of N,N-dimethylformamide were placed, and0.45 g (4.72 mmol) of sodium tert-butoxide was added thereto and themixture was stirred for 1 hour at 40° C. To this mixture, 5.1 mL of thetoluene solution containing 1.80 g (pure content: 1.41 g, 4.37 mmol) ofthe crude (3S)-4-chloro-3-methoxymethyloxy-butyl p-toluenesulfonateester (a compound of the formula (4), wherein X═Cl, P=methoxymethylgroup, and R²=p-tolyl group) obtained in Example 4-5 and 0.15 g (0.87mmol) of potassium iodide were added at 40° C. and the mixture wasstirred for 2 hours at 80° C. Toluene was added to this reaction liquidand the resulting reaction liquid was washed with water, dried, and thenconcentrated to obtain 2.08 g (pure content: 1.45 g; yield: 90%) ofdiethyl (3S)-2-acetylamino-2-(4-chloro-3-methoxymethyloxy-butyl)malonateester (a compound of the formula (6), wherein X ═Cl, P=methoxymethylgroup, R³=ethyl group, and A=methyl group).

[Example 8-1] Production of diethyl(3S)-2-benzoylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, and R³=ethyl group, and A=phenyl group)

In a 30-mL reactor, 0.38 g (1.37 mmol) of diethyl benzoylaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=phenyl group) and 1.9 mL of N,N-dimethylformamide were placed, and0.13 g (1.37 mmol) sodium tert-butoxide was added thereto and themixture was stirred for 1 hour at room temperature. To this mixture, 1.9mL of the toluene solution containing 0.51 g (pure content: 0.39 g, 1.37mmol) of the crude (3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butylmethanesulfonate ester (a compound of the formula (4), wherein X═Cl,P=tetrahydropyranyl group, and R²=methyl group) obtained in Example 3and 0.09 g (0.55 mmol) of potassium iodide were added at roomtemperature and the mixture was stirred for 1 hour at 80° C. A smallvolume of aliquot was withdrawn from this reaction liquid and toluenewas added thereto and the resulting mixture was washed with water,dried, and then concentrated to obtain 27 mg of crude diethyl(3S)-2-benzoylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, and R³=ethyl group, and A=phenyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.20 (6H, m), 1.32-1.80 (8H, m), 1.97-2.20 (1H,m), 2.40-2.57 (1H, m), 3.16-3.92 (5H, m), 4.20 (4H, m), 4.52 and 4.65(1H, m), 7.30 (3H, m), 7.80 (2H, m).

[Example 8-2] Production of diethyl(3S)-2-benzoylamino-2-[4-chloro-3-(methoxymethyloxy-butyl]malonate ester(a Compound of the Formula (6), Wherein X ═Cl, P=Methoxymethyl Group,R³=Ethyl Group, and A=Phenyl Group)

In a 50-mL reactor, 1.87 g (6.69 mmol) of diethyl benzoylaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=phenyl group) and 5.7 mL of N,N-dimethylformamide were placed, and0.63 g (6.57 mmol) of sodium tert-butoxide was added thereto and themixture was stirred for 1 hour at 40° C. To this mixture, 6 mL of thetoluene solution containing 1.50 g (6.08 mmol) of the crude(3S)-4-chloro-3-(tetrahydropyran-2-yloxy)-butyl methanesulfonate ester(a compound of the formula (4), wherein X═Cl, P=methoxymethyl group, andR²=methyl group) obtained in Example 3 and 0.20 g (1.22 mmol) ofpotassium iodide were added at 40° C. and the mixture was stirred for 2hours at 80° C. Toluene was added to this reaction liquid and theresulting reaction liquid was washed with water, dried, and thenconcentrated to obtain 2.83 g (pure content: 2.20 g; yield: 84%) ofcrude diethyl(3S)-2-benzoylamino-2-[4-chloro-3-methoxymethyloxy-butyl]malonate ester(a compound of the formula (6), wherein X═Cl, P=methoxymethyl group,R³=ethyl group, and A=phenyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.26 (6H, t, J=7.5 Hz), 1.20-1.85 (8H, m),2.45-2.65 (2H, m), 3.40-3.92 (5H, m), 4.29 (4H, m), 4.60 and 4.71 (1H,m), 7.42-7.55 (4H, m), 7.82 (2H, m).

[Example 8-3] Production of diethyl(3S)-2-benzoylamino-2-[4-chloro-3-(1-ethoxyethyloxy)-butyl]malonateester (a Compound of the Formula (6), Wherein X═Cl, P=Ethoxyethyl Group,R=Ethyl Group, and A=Phenyl Group)

In a 30-mL reactor, 2.31 g (8.27 mmol) of diethyl benzoylaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=phenyl group) and 8 mL of N,N-dimethylformamide were placed, and 0.78g (8.12 mmol) of sodium tert-butoxide was added thereto and the mixturewas stirred for 2 hours at 40° C. To this mixture, 4 mL of the toluenesolution containing 2.06 g (pure content: 1.99 g, 7.52 mmol) of thecrude (3S)-4-chloro-3-(1-ethoxyethyloxy)-butyl methanesulfonate ester (acompound of the formula (4), wherein X═Cl, P=ethoxyethyl group, andR²=methyl group) obtained in accordance with Example 4-2 and 0.25 g(1.50 mmol) of potassium iodide were added at 40° C. and the mixture wasstirred for 4.5 hours at 80° C. Toluene was added to this reactionliquid and the resulting reaction liquid was washed with water, dried,then concentrated, and purified by silica gel chromatography to obtain2.31 g of diethyl(3S)-2-benzoylamino-2-[4-chloro-3-(1-ethoxyethyloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=ethoxyethyl group,R³=ethyl group, and A=phenyl group) (yield: 67%).

¹H-NMR (400 MHz, CDCl₃) δ1.13-1.35 (12H, m), 1.40-1.63 (2H, m),2.45-2.65 (2H, m), 3.43-3.83 (5H, m), 4.30 (4H, m), 4.72 and 4.80 (1H,m), 7.43-7.58 (4H, m), 7.83 (2H, m).

[Example 8-4] Production of diethyl(3S)-2-benzoylamino-2-[4-chloro-3-tert-butyldimethylsilyloxy-butyl]malonateester (a Compound of the Formula (6), Wherein X═Cl,P=tert-butyldimethylsilyl Group, R³=Ethyl Group, and A=Phenyl Group)

In a 30-mL reactor, 1.48 g (5.29 mmol) of diethyl benzoylaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=phenyl group) and 6.8 mL of N,N-dimethylformamide were placed, and0.50 g (5.19 mmol) of sodium tert-butoxide was added thereto and themixture was stirred for 1 hour at 40° C. To this mixture, 1 mL of thetoluene solution containing 1.70 g (pure content: 1.52 g, 4.81 mmol) ofthe crude (3S)-4-chloro-3-tert-butyldimethylsilyloxy-butylmethanesulfonate ester (a compound of the formula (4), wherein X═Cl,P=tert-butyldimethylsilyl group, and R²=methyl group) obtained inExample 4-3 and 0.16 g (0.96 mmol) of potassium iodide were added at 40°C. and the mixture was stirred for 4.5 hours at 80° C. Toluene was addedto this reaction liquid and the resulting reaction liquid was washedwith water, dried, and then concentrated to obtain 2.68 g of crudediethyl(3S)-2-benzoylamino-2-[4-chloro-3-tert-butyldimethylsilyloxy-butyl]malonateester (a compound of the formula (6), wherein X═Cl,P=tert-butyldimethylsilyl group, R³=ethyl group, and A=phenyl group)(pure content: 1.95 g; yield: 81%).

¹H-NMR (400 MHz, CDCl₃) δ0.10 (6H, s), 0.90 (9H, s), 1.30 (6H, t, J=8.3Hz), 1.35-1.65 (2H, m), 2.48-2.65 (2H, m), 3.43 (2H, m), 3.85 (1H, m),4.33 (4H, m), 7.45-7.60 (4H, m), 7.84 (2H, m).

[Example 8-5] Production of diethyl(3S)-2-benzoylamino-2-[4-chloro-3-tert-butyloxy-butyl]malonate ester (aCompound of the Formula (6), Wherein X═Cl, P=Tert-Butyl Group, R³=EthylGroup, and A=Phenyl Group)

In a 50-mL reactor, 1.12 g (4.00 mmol) of diethyl benzoylaminomalonateester (a compound of the formula (5), wherein R³=ethyl group andA=phenyl group) and 4.4 mL of N,N-dimethylformamide were placed, and0.38 g (3.92 mmol) of sodium tert-butoxide was added thereto and themixture was stirred for 1 hour at 40° C. To this mixture, 2 mL of thetoluene solution containing 1.25 g (pure content: 0.94 g, 3.64 mmol) ofthe crude (3S)methanesulfonic acid 4-chloro-3-tert-butyloxy-butyl ester(a compound of the formula (4), wherein X═Cl, P=tert-butyl group, andR²=methyl group) obtained in Example 4-4 and 0.12 g (0.73 mmol) ofpotassium iodide were added at 40° C. and the mixture was stirred for 2hours at 80° C. Toluene was added to this reaction liquid and theresulting reaction liquid was washed with water, dried, thenconcentrated, and purified by silica gel chromatography to obtain 1.24 gof diethyl(3S)-2-benzoylamino-2-[4-chloro-3-tert-butyloxy-butyl]malonate ester (acompound of the formula (6), wherein X═Cl, P=tert-butyl group, R³=ethylgroup, and A=phenyl group) (pure content: 1.10 g; yield: 69%).

¹H-NMR (400 MHz, CDCl₃) δ1.16 (9H, s), 1.25-1.29 (7H, m), 1.31-1.42 (1H,m), 2.48-2.57 (2H, m), 3.34-3.49 (2H, m), 3.65 (1H, m), 4.28 (4H, q,J=6.8 Hz), 7.44-7.53 (4H, m), 7.81 (2H, m).

[Example 9] Production of diethyl(5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tetrahydropyranyl group,R³=ethyl group, and A=methyl group)

In a 100-mL reactor, 5.08 g (pure content: 4.35 g, 10.68 mmol) of thecrude diethyl(3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, R³=ethyl group, and A=methyl group) obtained in Example 5, 40 mLof dimethylformamide and 10.44 g (32.04 mmol) of cesium carbonate wereplaced and the mixture was stirred for 7 hours at 100° C. Toluene wasadded to this reaction liquid and the resulting reaction liquid waswashed with water, dried, and then concentrated to obtain 4.18 g ofcrude diethyl(5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tetrahydropyranyl group,R³=ethyl group, and A=methyl group) (yield: 94%).

¹H-NMR (400 MHz, CDCl₃) δ1.15-1.25 (6H, m), 1.32-1.95 (8H, m), 1.95-2.10(1H, m), 2.10 (3H, s), 2.40-2.50 (1H, m), 3.02 and 3.22 (1H, m), 3.43(1H, m), 3.55-3.70 (1H, m), 3.72-3.88 (2H, m), 4.10-4.25 (4H, m), 4.65(1H, m).

[Example 10] Production of diethyl(5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a Compound of the Formula (7), Wherein P=Tetrahydropyranyl Group,R³=Ethyl Group, and A=Methyl Group)

In a 100-mL reactor, 5.77 g (pure content: 4.95 g, 12.14 mmol) of thecrude diethyl(3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, R³=ethyl group, and A=methyl group) obtained in Example 5 and 58mL of dimethylformamide were placed and 1.52 g (15.78 mmol) of sodiumtert-butoxide were placed therein in three portions over 3 hours at 15°C. and the mixture was stirred for 2 hours at 15° C. An excess amount ofthe base was neutralized by adding 0.22 mL of acetic acid to thisreaction liquid, toluene was added thereto, and the resulting mixturewas washed with water, dried, and then concentrated to obtain 3.85 g(pure content: 2.77 g; yield: 62%) of crude diethyl(5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tetrahydropyranyl group,R³=ethyl group, and A=methyl group).

[Example 11-1] Production of diethyl(5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a Compound of the Formula (7), Wherein P=Tetrahydropyranyl Group,R³=Ethyl Group, and A=Methyl Group)

In a 10-mL reactor, 0.53 g (pure content: 0.5 g, 1.23 mmol) of the crudediethyl(3S)-2-acetylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, R³=ethyl group, and A=methyl group) obtained in Example 5 and 2.7mL of dimethylformamide were placed, and potassium carbonate (1.23 mmol)and tetrabutylammonium bromide (hereinafter referred to as “TBAB”)(1.227 mmol) were placed therein and the mixture was stirred for 15hours at 100° C.

Toluene was added to the mixture and the resulting mixture was washedwith brine, dried, and then concentrated to obtain 0.61 g (pure content:0.37 g; yield: 80%) of diethyl(5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tetrahydropyranyl group,R³=ethyl group, and A=methyl group).

[Example 11-2] Production of diethyl(5S)-1-acetyl-5-methoxymethyloxy-piperidine-2,2-dicarboxylate ester (aCompound of the Formula (7), Wherein P=Methoxymethyl Group, R³=EthylGroup, and A=Methyl Group)

In a 50-mL reactor, 1.41 g (pure content: 1.12 g, 3.04 mmol) of thecrude diethyl(3S)-2-acetylamino-2-[4-chloro-3-methoxymethyloxy-butyl]malonate ester(a compound of the formula (6), wherein X═Cl, P=methoxymethyl group,R³=ethyl group, and A=methyl group) obtained in accordance with Example7, 5.3 mL of dimethylformamide and 2.97 g (9.12 mmol) of cesiumcarbonate were placed and the mixture was stirred for 3 hours at 100° C.Toluene was added to this reaction liquid and the resulting reactionliquid was washed with water, dried, and then concentrated to obtain0.95 g (pure content: 0.87 g; yield: 87%) of crude diethyl(5S)-1-acetyl-5-methoxymethyloxy-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=methoxymethyl group, R³=ethylgroup, and A=methyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.27-1.31 (6H, m), 1.50-1.59 (1H, m), 1.80-1.90(1H, m), 2.08-2.17 (1H, m), 2.17 (3H, s), 2.48-2.55 (1H, m), 3.28-3.40(1H, m), 3.40 (3H, s), 3.63 (1H, m), 3.76 (1H, m), 4.18-4.30 (4H, m),4.71 (2H, m).

[Example 11-3] Production of diethyl(5S)-1-acetyl-5-(1-ethoxyethyloxy)-piperidine-2,2-dicarboxylate ester (aCompound of the Formula (7), Wherein P=Ethoxyethyl Group, R³=EthylGroup, and A=Methyl Group)

In a 100-mL reactor, 7.64 g (pure content: 7.14 g, 18.06 mmol) of thecrude diethyl(3S)-2-acetylamino-2-[4-chloro-3-(1-ethoxyethyloxy)-butyl]malonate ester(a compound of the formula (6), wherein X═Cl, P=ethoxyethyl group,R³=ethyl group, and A=methyl group) obtained in Example 7-2 and 17.1 mLof dimethylformamide were placed, and 853 mg (21.40 mmol) of 60% sodiumhydride was added portion-wise over 5 hours at 40° C. To this reactionliquid, 0.43 mL of acetic acid and toluene were added, and the resultingmixture was washed with water and aqueous 2% potassium carbonate, dried,and then concentrated to obtain 5.64 g (pure content: 5.31 g; yield:77%) of crude diethyl(5S)-1-acetyl-5-(1-ethoxyethyloxy)-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=ethoxyethyl group, R³=ethylgroup, and A=methyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.20-1.35 (12H, m), 1.35-1.50 (1H, m), 1.90(1H, m), 2.03-2.12 (1H, m), 2.14 (3H, s), 2.47-2.55 (1H, m), 3.02-3.15and 3.44-3.86 (5H, m), 4.20-4.35 (4H, m), 4.81 (1H, m).

[Example 11-4] Production of diethyl(5S)-1-acetyl-5-tert-butyldimethylsilyloxy-piperidine-2,2-dicarboxylateester (a Compound of the Formula (7), Wherein P=tert-butyldimethylsilylGroup, R³=Ethyl Group, and A=Methyl Group)

In a 50-mL reactor, 2.10 g (pure content: 1.77 g, 4.05 mmol) of thecrude diethyl(3S)-2-acetylamino-2-[4-chloro-3-tert-butyldimethylsilyloxy-butyl]malonateester (a compound of the formula (6), wherein X═Cl,P=tert-butyldimethylsilyl group, R³=ethyl group, and A=methyl group)obtained in Example 7-3, 8.4 mL of dimethylformamide and 3.96 g (12.15mmol) of cesium carbonate were placed and the mixture was stirred for 3hours at 100° C. Toluene was added to this reaction liquid and theresulting reaction liquid was washed with water, dried, thenconcentrated, and purified by silica gel chromatography to obtain 1.18 g(pure content: 1.13 g; yield: 70%) of diethyl(5S)-1-acetyl-5-tert-butyldimethylsilyloxy-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tert-butyldimethylsilylgroup, R³=ethyl group, and A=methyl group).

¹H-NMR (400 MHz, CDCl₃) δ0.09 (3H, s), 0.10 (3H, s), 0.90 (9H, s),1.25-1.30 (6H, m), 1.30-1.40 (1H, m), 1.75-1.85 (1H, m), 2.03-2.10 (1H,m), 2.15 (3H, s), 2.49-2.58 (1H, m), 3.02 (1H, dd, J=10.6, 12.1 Hz),3.58 (1H, dd, J=3.0, 12.1 Hz), 3.83 (1H, m), 4.17-4.31 (4H, m).

[Example 11-5] Production of diethyl(5S)-1-acetyl-5-tert-butyloxy-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=tert-butyl group, R³=ethyl group,and A=methyl group)

In a 50-mL reactor, 1.06 g (pure content: 0.95 g, 2.50 mmol) of thecrude (3S)-2-acetylamino-2-[4-chloro-3-tert-butyloxy-butyl]malonatediethyl ester (a compound of the formula (6), wherein X═Cl, P=tert-butylgroup, R³=ethyl group, and A=methyl group) obtained in Example 7-4, 4 mLof dimethylformamide and 2.44 g (7.50 mmol) of cesium carbonate wereplaced and the mixture was stirred for 4 hours at 100° C. Toluene wasadded to this reaction liquid and the resulting reaction liquid waswashed with water, dried, and then concentrated to obtain 0.73 g (purecontent: 0.64 g; yield: 75%) of diethyl(5S)-1-acetyl-5-tert-butyloxy-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=ten-butyl group, R³=ethyl group,and A=methyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.22 (9H, s), 1.25-1.32 (6H, m), 1.35 (1H, m),1.83-1.87 (1H, m), 2.00-2.07 (1H, m), 2.15 (3H, s), 2.50-2.56 (1H, m),2.85-2.91 (1H, m), 3.63-3.66 (2H, m), 4.20-4.27 (4H, m).

[Example 11-6] Production of diethyl(5S)-1-benzoyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a Compound of the Formula (7), Wherein P=Tetrahydropyranyl Group,R³=Ethyl Group, and A=Phenyl Group)

In a 50-mL reactor, 3.09 g (6.57 mmol) of the crude diethyl(3S)-2-benzoylamino-2-[4-chloro-3-(tetrahydropyran-2-yloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tetrahydropyranylgroup, and R³=ethyl group, and A=phenyl group) obtained in accordancewith Example 8, 12 mL of dimethylformamide and 6.42 g (19.71 mmol) ofcesium carbonate were placed and the mixture was stirred for 4.5 hoursat 100° C. Toluene was added to this reaction liquid and the resultingreaction liquid was washed with water, dried, then concentrated, andpurified by silica gel chromatography to obtain 2.08 g (pure content:1.88 g; yield: 66%) of diethyl(5S)-1-benzoyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tetrahydropyranyl group,R³=ethyl group, and A=phenyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.23-1.35 (6H, m), 1.43-1.95 (8H, m), 2.20-2.31(1H, m), 2.57-2.69 (1H, m), 3.22-3.89 (5H, m), 4.22-4.32 (4H, m), 4.50and 4.69 (1H, m) 7.40 (3H, m), 7.53-7.61 (2H, m).

[Example 11-7] Production of diethyl(5S)-1-benzoyl-5-methoxymethyloxy-piperidine-2,2-dicarboxylate ester (aCompound of the Formula (7), Wherein P=Methoxymethyl Group, R³=EthylGroup, and A=Phenyl Group)

In a 50-mL reactor, 1.42 g (pure content: 1.10 g, 2.56 mmol) of thecrude diethyl(3S)-2-benzoylamino-2-[4-chloro-3-methoxymethyloxy)-butyl]malonate ester(a compound of the formula (6), wherein X═Cl, P=methoxymethyl group,R³=ethyl group, and A=phenyl group) obtained in accordance with Example8-2, 5.2 mL of dimethylformamide and 2.50 g (7.68 mmol) of cesiumcarbonate were placed and the mixture was stirred for 3 hours at 100° C.Toluene was added to this reaction liquid and the resulting reactionliquid was washed with water, dried, and then concentrated to obtain0.99 g (pure content: 0.93 g; yield: 92%) of diethyl(5S)-1-benzoyl-5-methoxymethyloxy-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=methoxymethyl group, R³=ethylgroup, and A=phenyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.29-1.34 (6H, m), 1.58-1.68 (1H, m), 1.81-1.90(1H, m), 2.21-2.30 (1H, m), 2.55-2.65 (1H, m), 3.20-3.30 (1H, m), 3.28(3H, s), 3.40 (1H, m), 3.58 (1H, dd, J=3.2, 14.0 Hz), 3.75 (1H, m),4.20-4.39 (4H, m), 4.54 and 4.63 (1H, d, J=7.2 Hz), 7.42 (3H, m), 7.55(2H, m).

[Example 11-8] Production of diethyl(5S)-1-benzoyl-5-(l-ethoxyethyloxy)-piperidine-2,2-dicarboxylate ester(a Compound of the Formula (7), Wherein P=Ethoxyethyl Group, R³=EthylGroup, and A=Phenyl Group)

In a 50-mL reactor, 2.31 g (5.04 mmol) of the diethyl(3S)-2-benzoylamino-2-[4-chloro-3-(1-ethoxyethyloxy)-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=ethoxyethyl group,R³=ethyl group, and A=phenyl group) obtained in Example 8-3, 9.2 mL ofdimethylformamide and 4.93 g (15.12 mmol) of cesium carbonate wereplaced and the mixture was stirred for 5 hours at 100° C. Toluene wasadded to this reaction liquid and the resulting reaction liquid waswashed with water, dried, and then concentrated to obtain 0.92 g ofdiethyl (5S)-1-benzoyl-5-(l-ethoxyethyloxy)-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=ethoxyethyl group,R³=ethyl group, and A=phenyl group) (yield: 43%).

¹H-NMR (400 MHz, CDCl₃) δ0.99-1.10 (3H, m), 1.17-1.35 (9H, m), 1.45-1.60(1H, m), 1.83-1.92 (1H, m), 2.18-2.26 (1H, m), 2.57-2.65 (1H, m), 3.11(1H, m), 4.20-4.33 (4H, m), 4.61 and 4.73 (1H, m), 7.40 (3H, m), 7.52(2H, m).

[Example 11-9] Production of diethyl(5S)-1-benzoyl-5-tert-butyldimethylsilyloxy-piperidine-2,2-dicarboxylateester (a Compound of the Formula (7), Wherein P=tert-butyldimethylsilylGroup, R³=Ethyl Group, and A=Phenyl Group)

In a 50-mL reactor, 2.68 g (pure content: 1.95 g, 3.91 mmol) of thediethyl(3S)-2-benzoylamino-2-[4-chloro-3-tert-butyldimethylsilyloxy-butyl]malonateester (a compound of the formula (6), wherein X═Cl,P=tert-butyldimethylsilyl group, R³=ethyl group, and A=phenyl group)obtained in Example 8-4, 10.7 mL of dimethylformamide, 3.82 g of cesiumcarbonate (11.73 mmol) were placed and the mixture was stirred for 3hours at 100° C. Toluene was added to this reaction liquid and theresulting reaction liquid was washed with water, dried, thenconcentrated, and purified by silica gel chromatography to obtain 1.70 g(pure content: 1.45 g; yield: 80%) of diethyl(5S)-1-benzoyl-5-tert-butyldimethylsilyloxy-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tert-butyldimethylsilylgroup, R³=ethyl group, and A=phenyl group).

¹H-NMR (400 MHz, CDCl₃) δ0.02 (3H, s), 0.03 (3H, s), 0.90 (9H, s), 1.32(6H, m), 1.50-1.59 (1H, m), 1.77-1.85 (1H, m), 2.20-2.30 (1H, m),2.62-2.70 (1H, m), 3.16 (1H, dd, J=6.9, 12.0 Hz), 3.50 (1H, dd, J=1.7,13.7 Hz), 3.83 (1H, m), 4.23-4.37 (4H, m), 4.65 (1H, m), 7.42 (3H, m),7.58 (2H, m).

[Example 11-10] Production of diethyl(5S)-1-benzoyl-5-tert-butyloxy-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=tert-butyl group, R¹=ethyl group,and A=phenyl group)

In a 50-mL reactor, 1.24 g (pure content: 1.10 g, 2.50 mmol) of thediethyl (3 S)-2-benzoylamino-2-[4-chloro-3-tert-butyloxy-butyl]malonateester (a compound of the formula (6), wherein X═Cl, P=tert-butyl group,R³=ethyl group, and A=phenyl group) obtained in Example 8-5, 5 mL ofdimethylformamide and 2.44 g (7.50 mmol) of cesium carbonate were placedand the mixture was stirred for 4 hours at 100° C. Toluene was added tothis reaction liquid and the resulting reaction liquid was washed withwater, dried, and then concentrated to obtain 1.06 g (pure content: 0.84g; yield: 83%) of diethyl(5S)-1-benzoyl-5-tert-butyloxy-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=tert-butyl group, R³=ethyl group,and A=phenyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.11 (9H, s), 1.28-1.33 (6H, m), 1.42 (1H, m),1.80-1.86 (1H, m), 2.17-2.24 (1H, m), 2.60-2.66 (1H, m), 2.94-2.99 (1H,m), 3.56-3.63 (2H, m), 4.26-4.31 (4H, m), 7.38-7.43 (3H, m), 7.54 (2H,m).

[Example 12-1] Production of diethyl(5S)-1-acetyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a Compoundof the Formula (8), Wherein R¹=Ethyl Group and A=Methyl Group)

In a 100-mL reactor, 4.18 g (10.68 mmol) of the crude diethyl(5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tetrahydropyranyl group,R³=ethyl group, and A=methyl group) obtained in Example 10, 20 mL ofmethanol and 19 μL of concentrated hydrochloric acid were placed and themixture was stirred for 4 hours at room temperature. The reaction wasstopped by adding 45 μL of triethylamine to this reaction liquid andmethanol was concentrated under vacuum to obtain 3.7 g of an oilysubstance. Next, this oily substance was dissolved in 20 mL of toluene,10 mL of n-heptane was added thereto at room temperature forcrystallization and another 10 mL of n-heptane was added thereto toallow crystallization to proceed aging at room temperature, and then thecrystals were filtered, washed with n-heptane, and dried to obtain 2.30g of diethyl (5S)-1-acetyl-5-hydroxy-piperidine-2,2-dicarboxylate ester(a compound of the formula (8), wherein R³=ethyl group and A=methylgroup) (yield: 75%).

¹H-NMR (400 MHz, CDCl₃) δ1.20-1.30 (6H, m), 1.40-1.52 (1H, m), 1.80-1.90(1H, m), 2.09-2.15 (1H, m), 2.15 (3H, s), 2.40-2.50 (1H, m), 3.23 (1H,dd, J=7.6, 14.4 Hz), 3.57 (1H, dd, J=4.8, 12.8 Hz), 3.92 (1H, m),4.17-4.32 (4H, m).

[Example 12-2] Production of diethyl(5S)-1-acetyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a Compoundof the Formula (8), Wherein R³=Ethyl Group and A=Methyl Group)

In a 50-mL reactor, 1.45 g (pure content: 1.28 g, 3.57 mmol) of thecrude diethyl(5S)-1-acetyl-5-(1-ethoxyethyloxy)-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=ethoxyethyl group, R³=ethylgroup, and A=methyl group) obtained in Example 11-3, 7.25 mL of methanoland 10 μL of concentrated hydrochloric acid were placed and the mixturewas stirred for 4 hours at room temperature. This reaction liquid wasconcentrated under vacuum and purified by silica gel chromatography toobtain 0.79 g of diethyl(5S)-1-acetyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a compoundof the formula (8), wherein R³=ethyl group and A=methyl group) (yield:77%).

[Example 12-3] Production of diethyl(5S)-1-acetyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a Compoundof the Formula (8), Wherein R³=Ethyl Group and A=Methyl Group)

In a 10-mL reactor, 355 mg (pure content: 342 mg, 0.85 mmol) of thecrude(5S)-1-acetyl-5-tert-butyldimethylsilyloxy-piperidine-2,2-dicarboxylatediethyl ester (a compound of the formula (7), whereinP=tert-butyldimethylsilyl group, R³=ethyl group, and A=methyl group)obtained in Example 11-4, 2 mL of methanol and 20 μL of 20% hydrochloricacid were placed and the mixture was stirred for 28.5 hours at roomtemperature. This reaction liquid was concentrated under vacuum andpurified by silica gel chromatography to obtain 171 mg of diethyl(5S)-1-acetyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a compoundof the formula (8), wherein R³=ethyl group and A=methyl group) (yield:70%).

[Example 12-4] Production of diethyl(5S)-1-acetyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a Compoundof the Formula (8), Wherein R³=Ethyl Group and A=Methyl Group)

In a 10-mL reactor, 0.30 mg (pure content: 0.26 g, 0.77 mmol) of thecrude diethyl (5S)-1-acetyl-5-tert-butyloxy-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tert-butyl group,R³=ethyl group, and A=methyl group) obtained in Example 11-5, 1 mL oftoluene and 0.5 mL of trifluoroacetic acid were placed and the mixturewas stirred for 48.5 hours at room temperature. To this reaction liquid,1 mL of triethylamine was added, and the resulting reaction liquid waspurified by silica gel chromatography to obtain 0.14 g of diethyl(5S)-1-acetyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a compoundof the formula (8), wherein R³=ethyl group and A=methyl group) (yield:64%).

[Example 12-5] Production of diethyl(5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a Compoundof the Formula (8), Wherein R³=Ethyl Group and A=Phenyl Group)

In a 50-mL reactor, 2.08 g (pure content: 1.88 g, 4.33 mmol) of thecrude diethyl(5S)-1-benzoyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tetrahydropyranyl group,R³=ethyl group, and A=phenyl group) obtained in Example 11-6, 10 mL ofmethanol and 20 μL of concentrated hydrochloric acid were placed and themixture was stirred for 6 hours at room temperature. The reaction wasstopped by adding 100 μL of triethylamine to this reaction liquid, andmethanol was concentrated under vacuum, and the resulting mixture waspurified by silica gel chromatography to obtain 1.59 g (pure content:1.46 g; yield: 97%) of diethyl(5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a compoundof the formula (8), wherein R³=ethyl group and A=phenyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.29-1.35 (6H, m), 1.50-1.65 (1H, m), 1.82-1.90(1H, m), 2.05 (1H, brs), 2.25-2.33 (1H, m), 2.56-2.62 (1H, m), 3.30 (1H,dd, J=6.8, 13.6 Hz), 3.50 (1H, dd, J=3.2, 14.0 Hz), 3.89 (1H, m),4.21-4.38 (4H, m), 7.42 (3H, m), 7.52 (2H, m).

[Example 12-6] Production of diethyl(5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a Compoundof the Formula (8), Wherein R³=Ethyl Group and A=Phenyl Group)

In a 50-mL reactor, 0.38 g (pure content: 0.36 g, 0.92 mmol) of thecrude diethyl(5S)-1-benzoyl-5-methoxymethyloxy-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=methoxymethyl group, R³=ethylgroup, and A=phenyl group) obtained in Example 11-7, 5 mL of methanoland 50 μL of concentrated hydrochloric acid were placed and the mixturewas stirred for 4.5 hours at 70° C. This reaction liquid wasconcentrated under vacuum to obtain 0.30 g (pure content: 0.29 g; yield:91%) of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylateester (a compound of the formula (8), wherein R³=ethyl group andA=phenyl group).

[Example 12-7] Production of diethyl(5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a Compoundof the Formula (8), Wherein R³=Ethyl Group and A=Phenyl Group)

In a 50-mL reactor, 0.86 g (2.03 mmol) of the crude diethyl(5S)-1-benzoyl-5-(1-ethoxyethyloxy)-piperidine-2,2-dicarboxylate ester(a compound of the formula (7), wherein P=ethoxyethyl group, R³=ethylgroup, and A=phenyl group) obtained in Example 11-8, 4 mL of methanoland 10 μL of concentrated hydrochloric acid were placed and the mixturewas stirred for 4 hours at room temperature. The reaction was stopped byadding 100 μL of triethylamine to this reaction liquid, and methanol wasconcentrated under vacuum, and the resulting mixture was purified bysilica gel chromatography to obtain 0.68 g (pure content: 0.60 g; yield:85%) of diethyl (5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylateester (a compound of the formula (8), wherein R³=ethyl group andA=phenyl group).

[Example 12-8] Production of diethyl(5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a Compoundof the Formula (8), Wherein R³=Ethyl Group and A=Phenyl Group)

In a 50-mL reactor, 383 mg (pure content: 327 mg, 0.71 mmol) of thecrude(5S)1-benzoyl-5-tert-butyldimethylsilyloxy-piperidine-2,2-dicarboxylatediethyl ester (a compound of the formula (7), whereinP=tert-butyldimethylsilyl group, R³=ethyl group, and A=phenyl group)obtained in Example 11-9, 2 mL of methanol and 50 μL of 20% hydrochloricacid were placed and the mixture was stirred for 28.5 hours at roomtemperature. Then, methanol was concentrated under vacuum and theresulting mixture was purified by silica gel chromatography to obtain269 mg (pure content: 226 mg; yield: 91%) of diethyl(5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a compoundof the formula (8), wherein R³=ethyl group and A=phenyl group).

[Example 12-9] Production of diethyl(5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a Compoundof the Formula (8), Wherein R³=Ethyl Group and A=Phenyl Group)

In a 50-mL reactor, 0.29 g (pure content: 0.23 g, 0.57 mmol) of thecrude diethyl(5S)-1-benzoyl-5-tert-butyloxy-piperidine-2,2-dicarboxylate ester (acompound of the formula (7), wherein P=tert-butyl group, R³=ethyl group,and A=phenyl group) obtained in Example 11-10, 1 mL of toluene and 0.5mL of trifluoroacetic acid were placed and the mixture was stirred for48.5 hours at room temperature. Then, ethyl acetate was added theretoand the resulting mixture was washed with saturated aqueous sodiumbicarbonate solution, concentrated, and purified by silica gelchromatography to obtain 0.03 g of diethyl(5S)-1-benzoyl-5-hydroxy-piperidine-2,2-dicarboxylate ester (a compoundof the formula (8), wherein R³=ethyl group and A=phenyl group) (yield:15%).

[Example 13] Production of(2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (a Compound of theFormula (9), Wherein A=Methyl Group)

In a 200-mL reactor, 8.7 g (23.45 mmol) of the crude diethyl(5S)-1-acetyl-5-(tetrahydropyran-2-yloxy)-piperidine-2,2-dicarboxylateester (a compound of the formula (7), wherein P=tetrahydropyranyl group,R³=ethyl group, and A=methyl group) obtained in Example 10, 44 mL ofmethanol, 43.5 mL of toluene and 0.24 g of 35% hydrochloric acid wereplaced and the mixture was stirred for 3 hours at room temperature toobtain a solution of diethyl(5S)-1-acetyl-5-hydroxypiperidine-2,2-dicarboxylate ester (a compound ofthe formula (8), wherein R³=ethyl group and A=methyl group) in methanoland toluene. To this reaction liquid, 3.75 g of sodium hydroxide wasadded and the mixture was stirred for 3 hours, and methanol wasevaporated under vacuum to obtain a toluene solution. Next, 21.1 g ofacetic acid and 12.0 g of acetic anhydride were added to this solutionand the mixture was stirred for 1 hour at 50° C., 0.47 g oftriethylamine was further added thereto, and the mixture was heated to70° C. and stirred for 5 hours. This reaction liquid was cooled down to30° C. and 15 mL of toluene was added thereto for deposition and thedeposited sodium acetate was removed by filtration, and the filtrate wasconcentrated to obtain 2.83 g of(2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]ocan-3-one (a compound of theformula (9), wherein A=methyl group) (yield: 96%).

¹H-NMR (400 MHz, CDCl₃) δ1.78-2.23 (4H, m), 2.06 and 2.12 (3H, s), 3.55(1H, t, J=12.4 Hz), 3.65-3.77 (1H, m), 4.38 and 5.19 (1H, m), 4.83-4.90(1H, m).

[Example 14-1] Production of(2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (a Compound of theFormula (9), Wherein A=Methyl Group)

In a 500-mL reactor, 38.1 g (132.8 mmol) of the diethyl(5S)-1-acetyl-5-hydroxypiperidine-2,2-dicarboxylate ester (a compound ofthe formula (8), wherein R³=ethyl group and A=methyl group) obtained inExample 12, 190 mL of methanol and 21.2 g of sodium hydroxide wereplaced and the mixture was stirred for 3 hours at 50° C. to obtain asolution of (5S)-1-acetyl-5-hydroxypiperidine-2,2-dicarboxylic aciddisodium salt (compound (8) (a compound with R³═Na and A=methyl group)in methanol. To this reaction liquid, 119.5 g of acetic acid and 1.3 gof triethylamine were added and the mixture was stirred for 1 hour at95° C. to obtain a mixture of diastereomers of(5S)-1-acetyl-5-hydroxypiperidine-2-carboxylic acid (compounds (11c,11d)) in a mixed solution of acetic acid and methanol.

(2R,5S)-1-acetyl-5-hydroxypiperidine-2-carboxylic acid

¹H-NMR (400 MHz, D₂O) δ1.50-1.70 (2H, m), 1.85-2.10 (2H, m) 2.03 and2.10 (3H, s), 2.81 (0.3H, d, J=8.9 Hz), 3.35 (0.7H, d, J=8.9 Hz), 3.75(0.7H, d, J=8.9 Hz), 3.98 (1H, m), 4.26 (0.3H, d, J=8.9 Hz), 4.66 (0.3H,m), 5.08 (0.7H, m)

(2S,5S)-1-acetyl-5-hydroxypiperidine-2-carboxylic acid

¹H-NMR (400 MHz, D₂O) δ1.23-1.36 (1H, m), 1.59-1.81 (1H, m), 1.98 (1H,m), 2.10 and 2.19 (3H, s), 2.24-2.36 (1H, m), 2.54 (0.4H, t, J=12.6 Hz),3.03 (0.6H, dd, J=10.7 and 13.3 Hz), 3.55-3.65 (0.6H, m), 3.67-3.76(0.8H, m), 3.92 (0.6H, dd, J=5.3 and 13.3 Hz), 4.44 (0.6H, m), 4.47(0.4H, m), 4.94 (0.6H, m)

Next, methanol was evaporated under vacuum from the solution and 108 gof acetic anhydride was added thereto and the mixture was stirred for 3hours at 100° C. This reaction liquid was cooled down to 30° C. and 190mL of toluene was added thereto. The deposited sodium acetate wasremoved by filtration and the filtrate was concentrated to obtain 2.83 gof crude (2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (acompound of the formula (9), wherein A=methyl group) (yield: 72%).

[Example 14-2] Production of(2S,5S)-5-benzoyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (a Compound ofthe Formula (9), Wherein A=Phenyl Group)

In a 30-mL reactor, 1.29 g (3.68 mmol) of the diethyl(5S)1-benzoyl-5-hydroxypiperidine-2,2-dicarboxylate ester (a compound ofthe formula (8), wherein R³=ethyl group and A=phenyl group) obtained inaccordance with Example 12-5, 6.5 mL of methanol and 0.29 g (7.36 mmol)of sodium hydroxide were placed and the mixture was heated to reflux for2 hours and further heated for 14.5 hours after the addition of 0.15 g(3.68 mmol) of sodium hydroxide. Then, the mixture was adjusted on iceto pH 1 with aqueous sulfuric acid solution and the produced inorganicsalt was removed by filtration. The mixture was adjusted to pH 2 byaddition of sodium acetate and subsequently methanol and water wereconcentrated to obtain a mixture of diastereomers of(5S)-1-benzoyl-5-hydroxypiperidine-2-carboxylic acid (compounds (11e,11f)) in a white solid.

(2R,5S)-1-benzoyl-5-hydroxypiperidine-2-carboxylic acid

¹H-NMR (400 MHz, D₂O) δ1.33-1.85 (2H, m), 2.20 (2H, m), 3.12 (0.5H, d,J=15.0 Hz), 3.40 (0.5H, m), 3.50-3.90 (1H, m), 4.09 (0.5H, brs), 4.47(0.5H, m), 4.60 (0.5H, d, J=15.0 Hz), 5.46 (0.5H, m), 7.40-7.50 (5H, m).

(2S,5S)-1-benzoyl-5-hydroxypiperidine-2-carboxylic acid

¹H-NMR (400 MHz, D₂O) δ1.33-1.46 (1H, m), 1.65 (0.4H, m), 1.81 (0.6H,m), 2.02 (1H, m), 2.30 (0.4H, m), 2.43 (0.6H, m), 2.72 (0.4H, t, J=12.0Hz), 3.03 (0.6H, t, J=12.0 Hz), 3.58 (0.6H, m), 3.65 (0.4H, m), 3.80(0.6H, m), 4.40 (0.4H, m), 4.65 (0.4H, m), 5.40 (0.6H, m), 7.40 (5H, m).

Next, 1.32 mL of acetic acid (22.08 mmol), 5.2 mL of toluene, 0.04 g(0.37 mmol) of triethylamine and 0.57 g (6.38 mmol) of acetic anhydridewere added to the white solid and the mixture was stirred for 2.5 hoursat 90° C. This reaction liquid was concentrated and toluene was addedthereto. The deposited sodium acetate was removed by filtration, and thefiltrate was concentrated and purified by silica gel chromatography toobtain 0.76 g (pure content: 0.65 g; yield: 76%) of(2S,5S)-5-benzoyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (a compound ofthe formula (9), wherein A=phenyl group).

¹H-NMR (400 MHz, CDCl₃) δ1.88-2.30 (4H, m), 3.70 (1H, m), 3.90 (1H, m),4.45 and 4.79 (1H, brs), 4.98 and 5.27 (1H, brs), 7.45 (5H, m).

[Example 15] Production of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid(the Compound (10))

In a 200-mL reactor, 6.36 g (37.59 mmol) of the crude(2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (a compound of theformula (9), wherein A=methyl group) obtained in Example 13 and 93.98 mL(187.97 mmol) of 2 mol/L hydrochloric acid were placed and the mixturewas stirred for 3 hours at 90° C. This reaction liquid was concentratedand then dissolved again in water (42.9 mL) and allowed to be adsorbedon strong acidic cation exchange resin (88.69 mL). The resin was washedwith water and then elution was performed with ammonia water and theeluted fraction was concentrated to obtain crude(2S,5S)-5-hydroxy-piperidine-2-carboxylic acid (the compound (10)).

The obtained crude (2S,5S)-5-hydroxy-piperidine-2-carboxylic acid (thecompound (10)) was dissolved in water (10 mL) and 0.26 g of activatedcharcoal was added thereto and the mixture was stirred for 2 hours at40° C. The reaction liquid was filtered and then concentrated, andethanol was added to the residue to obtain crude crystals, and theobtained crystals were further recrystallized with water/ethanol/acetoneto obtain 1.61 g of (2S,5S)-5-hydroxy-piperidine-2-carboxylic acid (thecompound (10)) (purity: 96%; yield: 28%).

¹H-NMR (400 MHz, CD₃OD) δ1.73-1.90 (2H, m), 2.03-2.10 (2H, m), 3.09 (1H,dd, J=2.4, 12.8 Hz), 3.17-3.23 (1H, m), 3.45 (1H, m), 4.02 (1H, m).

[Example 16-1] Production of (2S,5S)-5-hydroxypiperidine-2-carboxylicacid (the Compound (10))

In a 1000-mL reactor, 18 g of an aqueous acetic acid solution containing11.31 g (66.90 mmol) of the crude(2S,5S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (in the formula(9), A=methyl group) prepared in accordance with Example 13 and 121 mLof 2 mol/L hydrochloric acid were placed and the mixture was stirred for3 hours at 90° C. To this reaction liquid, 1.2 g of activated charcoalwas added and the mixture was stirred for 1 hour at 45° C., and then theactivated charcoal was filtered and the filtrate was concentrated toobtain 20.5 g of a residue. Then, this residue was dissolved in 50 mL ofwater and 175 mL of DIAION®SAT10L (acetate anion type) resin was addedthereto and the mixture was stirred for 30 minutes at room temperatureand then filtered, and the filtrate was concentrated to obtain 16.5 g ofa residue. Then, 2.1 mL of water and 70 mL of ethanol were added to thisresidue for crystallization at 60° C. and the crystals were filtered atroom temperature and dried to obtain 8.0 g of crude crystals of(2S,5S)-5-hydroxy-piperidine-2-carboxylic acid (the compound (10))(purity: 93%; yield: 77%).

[Example 16-2] Production of (2S,5S)-5-hydroxypiperidine-2-carboxylicacid hydrochloride (a Hydrochloride of the Compound (10))

In a 10-mL reactor, 0.43 g (pure content: 0.36 g, 1.58 mmol) of the(2S,5S)-5-benzoyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one (in the formula(9), A=phenyl group) obtained in Example 14-2, 1.5 mL of water and 0.50g of 35% hydrochloric acid were placed and the mixture was stirred for15 hours at 100° C. The deposited benzoic acid was removed by filtrationand 11.38 g of the obtained filtrate was subjected to the quantificationby HPLC. Consequently, it was indicated that the filtrate contained 1.50mmol of (2S,5S)-5-hydroxypiperidine-2-carboxylic acid hydrochloride(yield: 95%).

1. A method for producing a compound represented by formula (9),

wherein A represents an alkyl group containing 1 to 10 carbon atoms, anaryl group containing 6 to 12 carbon atoms, an alkyloxy group containing1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbonatoms, the method comprising (i) removing the ether protecting groupfrom the hydroxyl group in the compound represented by formula (7)below:

wherein P represents an ether protecting group that is resistant tobasic reaction conditions, R³ represents an alkyl group containing 1 to4 carbon atoms, and A represents an alkyl group containing 1 to 10carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxygroup containing 1 to 4 carbon atoms, or an aralkyloxy group containing7 to 20 carbon atoms; to synthesize the compound represented by formula(8) below:

wherein R³ represents an alkyl group containing 1 to 4 carbon atoms, andA represents an alkyl group containing 1 to 10 carbon atoms, an arylgroup containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms;and (ii) (a) in the compound (8), hydrolyzing the ester groups, allowingone of the carboxyl groups to react with the hydroxyl group to allow thelactonization, and further decarboxylating the other carboxyl group; or(b) in the compound (8), hydrolyzing the ester groups, decarboxylatingone of the carboxyl groups to form a stereoisomeric mixture of a2-monocarboxylic acid, and then isomerizing and lactonizing thestereoisomeric mixture; to synthesize the compound represented by theformula (9) below:

wherein A represents an alkyl group containing 1 to 10 carbon atoms, anaryl group containing 6 to 12 carbon atoms, an alkyloxy group containing1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbonatoms.
 2. A compound represented by formula (9a) below:

wherein A′ represents an alkyl group containing 1 to 10 carbon atoms oran aryl group containing 6 to 12 carbon atoms.
 3. A compound representedby formula (6a) below:

wherein X represents C, Br, or I, P′ represents a tetrahydropyranylgroup, methoxymethyl group, ethoxyethyl group, tert-butyl group, ortert-butyldimethylsilyl group, and R³ represents an alkyl groupcontaining 1 to 4 carbon atoms, and A represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, an alkyloxy group containing 1 to 4 carbon atoms, or anaralkyloxy group containing 7 to 20 carbon atoms, or a compoundrepresented by formula (4a) below:

wherein X represents C, Br, or I, P′ represents a tetrahydropyranylgroup, methoxymethyl group, ethoxyethyl group, tert-butyl group, ortert-butyldimethylsilyl group, and R² represents an alkyl groupcontaining 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbonatoms, or an aralkyl group containing 7 to 20 carbon atoms, or acompound represented by formula (3a) below:

wherein X represents Cl, Br, or I, and P′ represents a tetrahydropyranylgroup, methoxymethyl group, ethoxyethyl group, tert-butyl group, ortert-butyldimethylsilyl group, or a compound represented by formula (2a)below:

wherein X represents Cl, Br, or I, R represents a hydrogen atom or anoptionally substituted alkyl group containing 1 to 4 carbon atoms, P″represents a tetrahydropyranyl group or ethoxyethyl group.